Modulators of androgen synthesis

ABSTRACT

The present specification discloses compositions comprising at least one therapeutic compound capable of modulating androgen production and methods and uses for treating a disorder associated with androgen production using such compositions and/or compounds.

This application is a divisional that claims the benefit of prioritypursuant to 35 U.S.C. §121 to U.S. patent application Ser. No.14/037,481, filed Sep. 26, 2013, a U.S. Non-Provisional patentapplication that claims the benefit of priority pursuant to 35 U.S.C.§119(e) to U.S. Provisional Patent Application 61/871,662, filed on Aug.29, 2013 and U.S. Provisional Patent Application 61/705,790, filed onSep. 26, 2012, each of which is hereby incorporated by reference in itsentirety.

BACKGROUND

Androgen is a generic term for any natural or synthetic compound (oftena steroid hormone). Androgens stimulate or control the development andmaintenance of male characteristics in vertebrates by binding toandrogen receptors. This includes the activity of the accessory male sexorgans and development of male secondary sex characteristics. Androgensare also the original anabolic steroids and the precursor of estrogens,the female sex hormones. The androgens include dihydrotestosteronetestosterone, androstenedione, androstenediol, anddehydroepiandrosterone.

Certain disorders or disease conditions are exacerbated by the presenceof androgens. One such example is a hormone-sensitive orhormone-dependent cancer. A hormone-sensitive or hormone-dependentcancer is one where the proliferation of tumor cells depends on thepresence of a hormone or its activity. Non-limiting examples ofhormone-dependent cancers include cancers of the breast, endometrium,prostate, ovary, testis, thyroid and bone. Other examples of ahormone-sensitive or hormone-dependent disorder include, withoutlimitation, a non-cancerous cell proliferation disorder like a uterinefibroid, a fibrocystic breast disease, an ovarian cyst, and prostateenlargement; abnormal uterine bleeding, amenorrhoea, premenstrualsyndrome (PMS), endometriosis, adenomyosis, and alopecia.

Hormone depletion therapy is the current treatment option available topeople diagnosed with certain hormone-sensitive or hormone-dependentdisorders, such as, e.g. a hormone-dependent cancer. The basic of thistherapy is that growth of a cancer can be reduced or halted by starvingtumor cells of a hormone inducing cell proliferation. Typically, this isachieved by reducing the overall systemic levels of a hormone, bypreventing the endogenous hormone from interacting with its cognatereceptor, or both. Although effective at first, most hormone dependentcancers become refractory after one to three years and resume growthdespite continued hormone depletion therapy. Once a hormone-sensitive orhormone-dependent disorder becomes hormone refractory, the treatmentoptions available to a patient are limited.

Thus, there is a still exists a need for the development ofpharmaceutical compositions and/or therapeutic compounds effective attreating a disorder associated with androgen production.

SUMMARY

Aspects of the present specification disclose compositions comprising atherapeutic compound capable of modulating androgen production.Therapeutic compounds include, without limitation, abenzo(iso)oxazolepiperidine, a fatty acid, a 5α reductase inhibitor, achemotherapeutic agent, an anti-proliferative agent, or any combinationthereof. The composition disclosed herein may reduce an unwanted sideand/or reduce a symptom of a disorder associated with androgenproduction.

Aspects of the present specification also disclose methods of treatingan individual with a disorder associated with androgen production. Thedisclosed methods comprising the step of administering to an individualin need thereof a pharmaceutical composition disclosed herein, whereinadministration reduces a symptom of a disorder associated with androgenproduction. A disorder associated with androgen production may be adisorder associated with steroid hydroxy-dehydrogenase activity, adisorder associated with HSD17B activity, a disorder associated withHSD17B10 activity, or any combination thereof. A disorder associatedwith androgen production may be a hormone-dependent disorder like ahormone-dependent proliferative disorder or a hormone-dependentnon-proliferative disorder. A disorder associated with androgenproduction may be a cancer, a hormone-refractory cancer, benignprostatic hyperplasia (BPH), polycystic ovary syndrome, acne vulgaris,seborrhea, female hirsutism, or androgenic alopecia. Administration of apharmaceutical composition may reduce the frequency of a symptom, thenumber of symptoms, the severity of a symptom, or any combinationthereof. Administration of a pharmaceutical composition may also reducean unwanted side in the individual.

Aspects of the present specification disclose uses of the disclosedcompositions and/or therapeutic compounds in the manufacture of amedicament for the treatment of a disorder associated with androgenproduction.

Aspects of the present specification disclose uses of the disclosedcompositions and/or therapeutic compounds in the treatment of a disorderassociated with androgen production.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the steroidogenesis pathway for sex hormones, including theenzymes involved in the pathway.

FIG. 2 shows the survival rate of animal groups treated with differentdrug and drug combinations.

FIG. 3 shows the tumor growth inhibition rate of animal groups treatedwith different drug and drug combinations.

DETAILED DESCRIPTION

Many patients treated with a hormone depletion therapy become resistantto this therapy. The present specification discloses that one possiblemechanism for why certain hormone-sensitive or hormone-dependentdisorders become refractory is the presence of a secondary pathway thatproduces the hormone or hormonal activity targeted for depletion. Forexample, prostate cancer is a hormone-dependent cancer and patientsdiagnosed with this cancer are typically treated using an androgendepletion therapy. However, many such patients become refractory to thistreatment after one to three years. One possible explanation for thistreatment resistance is the presence of an additional pathway thatbecomes responsible for generating testosterone (or dihydrotestosterone)in a manner useful to support proliferation of prostate tumor cells.

The present specification discloses compounds and pharmaceuticalcompositions comprising compounds that produce therapeutic effects inreducing a symptom of a disorder associated with androgen production. Inaspects of this embodiment, the therapeutic effect is achieved byreducing or inhibiting the activity facilitated by an alternative orsecondary pathway responsible for androgen production. In aspects ofthis embodiment, the therapeutic effect is achieved by reducing orinhibiting the activity facilitated by the primary pathway responsiblefor androgen production in addition to reducing or inhibiting theactivity facilitated by an alternative or secondary pathway responsiblefor androgen production.

Aspects of the present specification disclose, in part, a pharmaceuticalcomposition. As used herein, the term “pharmaceutical composition” issynonymous with “pharmaceutically acceptable composition” and refers toa therapeutically effective concentration of an active ingredient, suchas, e.g., any of the therapeutic compounds disclosed herein. As usedherein, the term “pharmaceutically acceptable” refers to any molecularentity or composition that does not produce an adverse, allergic orother untoward or unwanted reaction when administered to an individual.A pharmaceutical composition disclosed herein is useful for medical andveterinary applications. A pharmaceutical composition may beadministered to an individual alone, or in combination with othersupplementary active ingredients, agents, drugs or hormones.

A pharmaceutical composition disclosed herein may comprise one or moretherapeutic compounds disclosed herein. In one embodiment,pharmaceutical composition disclosed herein may comprise only a single atherapeutic disclosed herein. In another embodiment, pharmaceuticalcomposition disclosed herein may comprise a plurality of therapeuticcompounds disclosed herein. In aspects of this embodiment, apharmaceutical composition disclosed herein comprises at least onetherapeutic compound, at least two therapeutic compounds, at least threetherapeutic compounds, or at least four therapeutic compounds. In otheraspects of this embodiment, a pharmaceutical composition disclosedherein comprises at most two therapeutic compounds, at most threetherapeutic compounds, or at most four therapeutic compounds. In yetother aspects of this embodiment, a pharmaceutical composition disclosedherein comprises one to three therapeutic compounds, two to fourtherapeutic compounds, two to five therapeutic compounds, three to fivetherapeutic compounds, or two to three therapeutic compounds.

A pharmaceutical composition disclosed herein may reduce the occurrenceof an unwanted side effect elicited by administration of one or more ofthe therapeutic compounds contained in the pharmaceutical composition.Examples of an unwanted side effect, include, without limitation,feminization in males and defeminisation of females. Examples of malefeminization include, without limitation, chemical castration, decreasederections, reduced sexual desire, bone pain, breast tenderness,gynaecomastia, hot flushes, weight gain, gastrointestinal disorders,fatigue, headache, depression, nausea, hepatic changes includingelevated levels of transaminases and jaundice. Examples of femaledefeminisation include, without limitation, unwanted hair growth,increased risk for developing osteoporosis and joint disorders such asarthritis, arthrosis and arthralgia, infertility, aggressive behaviour,adrenal insufficiency, kidney failure, and liver dysfunction.

Aspects of the present specification disclose, in part, a therapeuticcompound. A therapeutic compound is a compound that providespharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease, or to affect thestructure or any function of the body of man or animals. Any suitableform of a therapeutic compound may be chosen. A therapeutic compounddisclosed herein may be used in the form of a pharmaceuticallyacceptable salt, solvate, or solvate of a salt, e.g. the hydrochloride.Additionally, therapeutic compound disclosed herein may be provided asracemates, or as individual enantiomers, including the R- orS-enantiomer. Thus, the therapeutic compound disclosed herein maycomprise a R-enantiomer only, a S-enantiomer only, or a combination ofboth a R-enantiomer and a S-enantiomer of a therapeutic compound. Atherapeutic compound disclosed herein may also be provided as prodrug oractive metabolite.

A therapeutic compound disclosed herein may reduce a symptom of adisorder associated with androgen production by, e.g., reducing asteroid hydroxy-dehydrogenase activity, reducing a 11β-hydroxysteroiddehydrogenase activity, reducing a symptom of a disorder associated witha 3β-hydroxysteroid dehydrogenase activity, reducing a17β-hydroxysteroid dehydrogenase activity, reducing a 20β-hydroxysteroiddehydrogenase activity, or any combination thereof. A therapeuticcompound disclosed herein may reduce a symptom of a disorder associatedwith androgen production by, e.g., reducing a level or an activity of adihydrotestosterone, reducing a level or an activity of a testosterone,reducing a level or an activity of an androstenedione, reducing a levelor an activity of an androstenediol, reducing a level or an activity ofa dehydroepiandrosterone, or any combination thereof.

In one embodiment, a therapeutic compound disclosed herein reduces asymptom of a disorder associated with androgen production. In aspects ofthis embodiment, a therapeutic compound disclosed herein reduces asymptom of a disorder associated with androgen production by, e.g., atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90% or at least 95%. In other aspects of thisembodiment, a therapeutic compound disclosed herein reduces a symptom ofa disorder associated with androgen production by, e.g., about 10% toabout 100%, about 20% to about 100%, about 30% to about 100%, about 40%to about 100%, about 50% to about 100%, about 60% to about 100%, about70% to about 100%, about 80% to about 100%, about 10% to about 90%,about 20% to about 90%, about 30% to about 90%, about 40% to about 90%,about 50% to about 90%, about 60% to about 90%, about 70% to about 90%,about 10% to about 80%, about 20% to about 80%, about 30% to about 80%,about 40% to about 80%, about 50% to about 80%, or about 60% to about80%, about 10% to about 70%, about 20% to about 70%, about 30% to about70%, about 40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein reducesthe frequency of a symptom of a disorder associated with androgenproduction incurred over a given time period. In aspects of thisembodiment, a therapeutic compound disclosed herein reduces thefrequency of a symptom of a disorder associated with androgen productionincurred over a given time period by, e.g., at least 10%, at least 15%,at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, atleast 45%, at least 50%, at least 55%, at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90% or atleast 95%. In other aspects of this embodiment, a therapeutic compounddisclosed herein reduces the frequency of a symptom of a disorderassociated with androgen production incurred over a given time periodby, e.g., about 10% to about 100%, about 20% to about 100%, about 30% toabout 100%, about 40% to about 100%, about 50% to about 100%, about 60%to about 100%, about 70% to about 100%, about 80% to about 100%, about10% to about 90%, about 20% to about 90%, about 30% to about 90%, about40% to about 90%, about 50% to about 90%, about 60% to about 90%, about70% to about 90%, about 10% to about 80%, about 20% to about 80%, about30% to about 80%, about 40% to about 80%, about 50% to about 80%, orabout 60% to about 80%, about 10% to about 70%, about 20% to about 70%,about 30% to about 70%, about 40% to about 70%, or about 50% to about70%.

In another embodiment, a therapeutic compound disclosed herein reducesthe number of symptoms of a disorder associated with androgen productionincurred over a given time period. In aspects of this embodiment, atherapeutic compound disclosed herein reduces the number of symptoms ofa disorder associated with androgen production incurred over a giventime period by, e.g., at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, at least 90% or at least 95%. In otheraspects of this embodiment, a therapeutic compound disclosed hereinreduces the number of symptoms of a disorder associated with androgenproduction incurred over a given time period by, e.g., about 10% toabout 100%, about 20% to about 100%, about 30% to about 100%, about 40%to about 100%, about 50% to about 100%, about 60% to about 100%, about70% to about 100%, about 80% to about 100%, about 10% to about 90%,about 20% to about 90%, about 30% to about 90%, about 40% to about 90%,about 50% to about 90%, about 60% to about 90%, about 70% to about 90%,about 10% to about 80%, about 20% to about 80%, about 30% to about 80%,about 40% to about 80%, about 50% to about 80%, or about 60% to about80%, about 10% to about 70%, about 20% to about 70%, about 30% to about70%, about 40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein reducesthe severity of a symptom of a disorder associated with androgenproduction. In aspects of this embodiment, a therapeutic compounddisclosed herein reduces the severity of a symptom of a disorderassociated with androgen production by, e.g., at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, at least 45%, at least 50%, at least 55%, at least 60%, at least65%, at least 70%, at least 75%, at least 80%, at least 85%, at least90% or at least 95%. In other aspects of this embodiment, a therapeuticcompound disclosed herein reduces the severity of a symptom of adisorder associated with androgen production by, e.g., about 10% toabout 100%, about 20% to about 100%, about 30% to about 100%, about 40%to about 100%, about 50% to about 100%, about 60% to about 100%, about70% to about 100%, about 80% to about 100%, about 10% to about 90%,about 20% to about 90%, about 30% to about 90%, about 40% to about 90%,about 50% to about 90%, about 60% to about 90%, about 70% to about 90%,about 10% to about 80%, about 20% to about 80%, about 30% to about 80%,about 40% to about 80%, about 50% to about 80%, or about 60% to about80%, about 10% to about 70%, about 20% to about 70%, about 30% to about70%, about 40% to about 70%, or about 50% to about 70%.

In one embodiment, a therapeutic compound disclosed herein reduces asymptom of a disorder associated with steroid hydroxy-dehydrogenaseactivity. In aspects of this embodiment, a therapeutic compounddisclosed herein reduces a symptom of a disorder associated with steroidhydroxy-dehydrogenase activity by, e.g., at least 10%, at least 15%, atleast 20%, at least 25%, at least 30%, at least 35%, at least 40%, atleast 45%, at least 50%, at least 55%, at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90% or atleast 95%. In other aspects of this embodiment, a therapeutic compounddisclosed herein reduces a symptom of a disorder associated with steroidhydroxy-dehydrogenase activity by, e.g., about 10% to about 100%, about20% to about 100%, about 30% to about 100%, about 40% to about 100%,about 50% to about 100%, about 60% to about 100%, about 70% to about100%, about 80% to about 100%, about 10% to about 90%, about 20% toabout 90%, about 30% to about 90%, about 40% to about 90%, about 50% toabout 90%, about 60% to about 90%, about 70% to about 90%, about 10% toabout 80%, about 20% to about 80%, about 30% to about 80%, about 40% toabout 80%, about 50% to about 80%, or about 60% to about 80%, about 10%to about 70%, about 20% to about 70%, about 30% to about 70%, about 40%to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein reducesthe frequency of a symptom of a disorder associated with steroidhydroxy-dehydrogenase activity incurred over a given time period. Inaspects of this embodiment, a therapeutic compound disclosed hereinreduces the frequency of a symptom of a disorder associated with steroidhydroxy-dehydrogenase activity incurred over a given time period by,e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90% or at least 95%. In other aspects ofthis embodiment, a therapeutic compound disclosed herein reduces thefrequency of a symptom of a disorder associated with steroidhydroxy-dehydrogenase activity incurred over a given time period by,e.g., about 10% to about 100%, about 20% to about 100%, about 30% toabout 100%, about 40% to about 100%, about 50% to about 100%, about 60%to about 100%, about 70% to about 100%, about 80% to about 100%, about10% to about 90%, about 20% to about 90%, about 30% to about 90%, about40% to about 90%, about 50% to about 90%, about 60% to about 90%, about70% to about 90%, about 10% to about 80%, about 20% to about 80%, about30% to about 80%, about 40% to about 80%, about 50% to about 80%, orabout 60% to about 80%, about 10% to about 70%, about 20% to about 70%,about 30% to about 70%, about 40% to about 70%, or about 50% to about70%.

In another embodiment, a therapeutic compound disclosed herein reducesthe number of symptoms of a disorder associated with steroidhydroxy-dehydrogenase activity incurred over a given time period. Inaspects of this embodiment, a therapeutic compound disclosed hereinreduces the number of symptoms of a disorder associated with steroidhydroxy-dehydrogenase activity incurred over a given time period by,e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90% or at least 95%. In other aspects ofthis embodiment, a therapeutic compound disclosed herein reduces thenumber of symptoms of a disorder associated with steroidhydroxy-dehydrogenase activity incurred over a given time period by,e.g., about 10% to about 100%, about 20% to about 100%, about 30% toabout 100%, about 40% to about 100%, about 50% to about 100%, about 60%to about 100%, about 70% to about 100%, about 80% to about 100%, about10% to about 90%, about 20% to about 90%, about 30% to about 90%, about40% to about 90%, about 50% to about 90%, about 60% to about 90%, about70% to about 90%, about 10% to about 80%, about 20% to about 80%, about30% to about 80%, about 40% to about 80%, about 50% to about 80%, orabout 60% to about 80%, about 10% to about 70%, about 20% to about 70%,about 30% to about 70%, about 40% to about 70%, or about 50% to about70%.

In another embodiment, a therapeutic compound disclosed herein reducesthe severity of a symptom of a disorder associated with steroidhydroxy-dehydrogenase activity. In aspects of this embodiment, atherapeutic compound disclosed herein reduces the severity of a symptomof a disorder associated with steroid hydroxy-dehydrogenase activity by,e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90% or at least 95%. In other aspects ofthis embodiment, a therapeutic compound disclosed herein reduces theseverity of a symptom of a disorder associated with steroidhydroxy-dehydrogenase activity by, e.g., about 10% to about 100%, about20% to about 100%, about 30% to about 100%, about 40% to about 100%,about 50% to about 100%, about 60% to about 100%, about 70% to about100%, about 80% to about 100%, about 10% to about 90%, about 20% toabout 90%, about 30% to about 90%, about 40% to about 90%, about 50% toabout 90%, about 60% to about 90%, about 70% to about 90%, about 10% toabout 80%, about 20% to about 80%, about 30% to about 80%, about 40% toabout 80%, about 50% to about 80%, or about 60% to about 80%, about 10%to about 70%, about 20% to about 70%, about 30% to about 70%, about 40%to about 70%, or about 50% to about 70%.

A therapeutic compound disclosed herein may be capable of modulating17β-Hydroxysteroid dehydrogenase (HSD17B) activity. As used herein, theterm “capable of modulating HSD17B activity” refers to the ability ofthe therapeutic compound disclosed herein to directly or indirectlyalter the oxidative activity of a HSD17B, directly or indirectly alterthe reductive activity of a HSD17B, directly or indirectly decrease thelevel of a progesterone in an individual, directly or indirectlydecrease the level of an androgen in an individual, directly orindirectly decrease the level of an estrogen in an individual, or anycombination thereof. Steroid hydroxy-dehydrogenases are a class ofenzyme involved in androgen production. 17β-hydroxysteroiddehydrogenases (17β HSDs or HSD17Bs) are responsible for oxidation andreduction of androgens via this bio-synthetic pathway. Most of theseenzymes are capable of working in both redox directions, butpredominantly carry out one reaction in vivo. HSD17β10 (HSD17B10 orHSD10) is known to be up-regulated in certain cancers as well as cancerthat have become hormone refractory.

In aspects of this embodiment, a therapeutic compound capable ofmodulating HSD17B activity includes, without limitation, a therapeuticcompound capable of modulating HSD17B subtype 1 (HSD17B1) activity atherapeutic compound capable of modulating HSD17B subtype 2 (HSD17B2)activity a therapeutic compound capable of modulating HSD17B subtype 3(HSD17B3) activity a therapeutic compound capable of modulating HSD17Bsubtype 4 (HSD17B4) activity a therapeutic compound capable ofmodulating HSD17B subtype 5 (HSD17B5) activity a therapeutic compoundcapable of modulating HSD17B subtype 6 (HSD17B6) activity a therapeuticcompound capable of modulating HSD17B subtype 7 (HSD17B7) activity atherapeutic compound capable of modulating HSD17B subtype 8 (HSD17B8)activity a therapeutic compound capable of modulating HSD17B subtype 9(HSD17B9) activity a therapeutic compound capable of modulating HSD17Bsubtype 10 (HSD17B10) activity a therapeutic compound capable ofmodulating HSD17B subtype 11 (HSD17B11) activity a therapeutic compoundcapable of modulating HSD17B subtype 12 (HSD17B12) activity atherapeutic compound capable of modulating HSD17B subtype 13 (HSD17B13)activity a therapeutic compound capable of modulating HSD17B subtype 14(HSD17B14) activity or a therapeutic compound capable of modulatingHSD17B subtype 15 (HSD17B15) activity.

In one embodiment, a therapeutic compound disclosed herein reduces asymptom of a disorder associated with HSD17B activity. In aspects ofthis embodiment, a therapeutic compound disclosed herein reduces asymptom of a disorder associated with HSD17B activity by, e.g., at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, at least 45%, at least 50%, at least 55%, at least60%, at least 65%, at least 70%, at least 75%, at least 80%, at least85%, at least 90% or at least 95%. In other aspects of this embodiment,a therapeutic compound disclosed herein reduces a symptom of a disorderassociated with HSD17B activity by, e.g., about 10% to about 100%, about20% to about 100%, about 30% to about 100%, about 40% to about 100%,about 50% to about 100%, about 60% to about 100%, about 70% to about100%, about 80% to about 100%, about 10% to about 90%, about 20% toabout 90%, about 30% to about 90%, about 40% to about 90%, about 50% toabout 90%, about 60% to about 90%, about 70% to about 90%, about 10% toabout 80%, about 20% to about 80%, about 30% to about 80%, about 40% toabout 80%, about 50% to about 80%, or about 60% to about 80%, about 10%to about 70%, about 20% to about 70%, about 30% to about 70%, about 40%to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein reducesthe frequency of a symptom of a disorder associated with HSD17B activityincurred over a given time period. In aspects of this embodiment, atherapeutic compound disclosed herein reduces the frequency of a symptomof a disorder associated with HSD17B activity incurred over a given timeperiod by, e.g., at least 10%, at least 15%, at least 20%, at least 25%,at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95%. In other aspectsof this embodiment, a therapeutic compound disclosed herein reduces thefrequency of a symptom of a disorder associated with HSD17B activityincurred over a given time period by, e.g., about 10% to about 100%,about 20% to about 100%, about 30% to about 100%, about 40% to about100%, about 50% to about 100%, about 60% to about 100%, about 70% toabout 100%, about 80% to about 100%, about 10% to about 90%, about 20%to about 90%, about 30% to about 90%, about 40% to about 90%, about 50%to about 90%, about 60% to about 90%, about 70% to about 90%, about 10%to about 80%, about 20% to about 80%, about 30% to about 80%, about 40%to about 80%, about 50% to about 80%, or about 60% to about 80%, about10% to about 70%, about 20% to about 70%, about 30% to about 70%, about40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein reducesthe number of symptoms of a disorder associated with HSD17B activityincurred over a given time period. In aspects of this embodiment, atherapeutic compound disclosed herein reduces the number of symptoms ofa disorder associated with HSD17B activity incurred over a given timeperiod by, e.g., at least 10%, at least 15%, at least 20%, at least 25%,at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95%. In other aspectsof this embodiment, a therapeutic compound disclosed herein reduces thenumber of symptoms of a disorder associated with HSD17B activityincurred over a given time period by, e.g., about 10% to about 100%,about 20% to about 100%, about 30% to about 100%, about 40% to about100%, about 50% to about 100%, about 60% to about 100%, about 70% toabout 100%, about 80% to about 100%, about 10% to about 90%, about 20%to about 90%, about 30% to about 90%, about 40% to about 90%, about 50%to about 90%, about 60% to about 90%, about 70% to about 90%, about 10%to about 80%, about 20% to about 80%, about 30% to about 80%, about 40%to about 80%, about 50% to about 80%, or about 60% to about 80%, about10% to about 70%, about 20% to about 70%, about 30% to about 70%, about40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein reducesthe severity of a symptom of a disorder associated with HSD17B activity.In aspects of this embodiment, a therapeutic compound disclosed hereinreduces the severity of a symptom of a disorder associated with HSD17Bactivity by, e.g., at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, at least 90% or at least 95%. In otheraspects of this embodiment, a therapeutic compound disclosed hereinreduces the severity of a symptom of a disorder associated with HSD17Bactivity by, e.g., about 10% to about 100%, about 20% to about 100%,about 30% to about 100%, about 40% to about 100%, about 50% to about100%, about 60% to about 100%, about 70% to about 100%, about 80% toabout 100%, about 10% to about 90%, about 20% to about 90%, about 30% toabout 90%, about 40% to about 90%, about 50% to about 90%, about 60% toabout 90%, about 70% to about 90%, about 10% to about 80%, about 20% toabout 80%, about 30% to about 80%, about 40% to about 80%, about 50% toabout 80%, or about 60% to about 80%, about 10% to about 70%, about 20%to about 70%, about 30% to about 70%, about 40% to about 70%, or about50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein reducesthe severity of a symptom of a disorder associated with HSD17B10 (orHSD10) enzymatic activity. In aspects of this embodiment, a therapeuticcompound disclosed herein reduces the severity of a symptom of adisorder associated with HSD17B10 enzymatic activity by, e.g., at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, at least 45%, at least 50%, at least 55%, at least60%, at least 65%, at least 70%, at least 75%, at least 80%, at least85%, at least 90% or at least 95%. In other aspects of this embodiment,a therapeutic compound disclosed herein reduces the severity of asymptom of a disorder associated with HSD17B10 enzymatic activity by,e.g., about 10% to about 100%, about 20% to about 100%, about 30% toabout 100%, about 40% to about 100%, about 50% to about 100%, about 60%to about 100%, about 70% to about 100%, about 80% to about 100%, about10% to about 90%, about 20% to about 90%, about 30% to about 90%, about40% to about 90%, about 50% to about 90%, about 60% to about 90%, about70% to about 90%, about 10% to about 80%, about 20% to about 80%, about30% to about 80%, about 40% to about 80%, about 50% to about 80%, orabout 60% to about 80%, about 10% to about 70%, about 20% to about 70%,about 30% to about 70%, about 40% to about 70%, or about 50% to about70%.

In another embodiment, a therapeutic compound disclosed herein modulatesandrogen production. In aspects of this embodiment, a therapeuticcompound disclosed herein modulates androgen production by, e.g., atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90% or at least 95%. In other aspects of thisembodiment, a therapeutic compound disclosed herein modulates androgenproduction by, e.g., about 10% to about 100%, about 20% to about 100%,about 30% to about 100%, about 40% to about 100%, about 50% to about100%, about 60% to about 100%, about 70% to about 100%, about 80% toabout 100%, about 10% to about 90%, about 20% to about 90%, about 30% toabout 90%, about 40% to about 90%, about 50% to about 90%, about 60% toabout 90%, about 70% to about 90%, about 10% to about 80%, about 20% toabout 80%, about 30% to about 80%, about 40% to about 80%, about 50% toabout 80%, or about 60% to about 80%, about 10% to about 70%, about 20%to about 70%, about 30% to about 70%, about 40% to about 70%, or about50% to about 70%. In yet other aspects of this embodiment, modulation ofandrogen production may include modulation of a steroidhydroxy-dehydrogenase activity. In still other aspects of thisembodiment, modulation of androgen production may include a11β-hydroxysteroid dehydrogenase activity, a 3β-hydroxysteroiddehydrogenase activity, a 17β-hydroxysteroid dehydrogenase activity, a20β-hydroxysteroid dehydrogenase activity, or any combination thereof.

In another embodiment, a therapeutic compound disclosed herein reduces alevel of a dihydrotestosterone. In aspects of this embodiment, atherapeutic compound disclosed herein reduces a level of adihydrotestosterone by, e.g., at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90% or at least 95%. Inother aspects of this embodiment, a therapeutic compound disclosedherein reduces a level of a dihydrotestosterone by, e.g., about 10% toabout 100%, about 20% to about 100%, about 30% to about 100%, about 40%to about 100%, about 50% to about 100%, about 60% to about 100%, about70% to about 100%, about 80% to about 100%, about 10% to about 90%,about 20% to about 90%, about 30% to about 90%, about 40% to about 90%,about 50% to about 90%, about 60% to about 90%, about 70% to about 90%,about 10% to about 80%, about 20% to about 80%, about 30% to about 80%,about 40% to about 80%, about 50% to about 80%, or about 60% to about80%, about 10% to about 70%, about 20% to about 70%, about 30% to about70%, about 40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein reduces alevel of a testosterone. In aspects of this embodiment, a therapeuticcompound disclosed herein reduces a level of a testosterone by, e.g., atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90% or at least 95%. In other aspects of thisembodiment, a therapeutic compound disclosed herein reduces a level of atestosterone by, e.g., about 10% to about 100%, about 20% to about 100%,about 30% to about 100%, about 40% to about 100%, about 50% to about100%, about 60% to about 100%, about 70% to about 100%, about 80% toabout 100%, about 10% to about 90%, about 20% to about 90%, about 30% toabout 90%, about 40% to about 90%, about 50% to about 90%, about 60% toabout 90%, about 70% to about 90%, about 10% to about 80%, about 20% toabout 80%, about 30% to about 80%, about 40% to about 80%, about 50% toabout 80%, or about 60% to about 80%, about 10% to about 70%, about 20%to about 70%, about 30% to about 70%, about 40% to about 70%, or about50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein reduces alevel of an androstenedione. In aspects of this embodiment, atherapeutic compound disclosed herein reduces a level of anandrostenedione by, e.g., at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90% or at least 95%. Inother aspects of this embodiment, a therapeutic compound disclosedherein reduces a level of an androstenedione by, e.g., about 10% toabout 100%, about 20% to about 100%, about 30% to about 100%, about 40%to about 100%, about 50% to about 100%, about 60% to about 100%, about70% to about 100%, about 80% to about 100%, about 10% to about 90%,about 20% to about 90%, about 30% to about 90%, about 40% to about 90%,about 50% to about 90%, about 60% to about 90%, about 70% to about 90%,about 10% to about 80%, about 20% to about 80%, about 30% to about 80%,about 40% to about 80%, about 50% to about 80%, or about 60% to about80%, about 10% to about 70%, about 20% to about 70%, about 30% to about70%, about 40% to about 70%, or about 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein reduces alevel of an androstenediol. In aspects of this embodiment, a therapeuticcompound disclosed herein reduces a level of an androstenediol by, e.g.,at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90% or at least 95%. In other aspects of thisembodiment, a therapeutic compound disclosed herein reduces a level ofan androstenediol by, e.g., about 10% to about 100%, about 20% to about100%, about 30% to about 100%, about 40% to about 100%, about 50% toabout 100%, about 60% to about 100%, about 70% to about 100%, about 80%to about 100%, about 10% to about 90%, about 20% to about 90%, about 30%to about 90%, about 40% to about 90%, about 50% to about 90%, about 60%to about 90%, about 70% to about 90%, about 10% to about 80%, about 20%to about 80%, about 30% to about 80%, about 40% to about 80%, about 50%to about 80%, or about 60% to about 80%, about 10% to about 70%, about20% to about 70%, about 30% to about 70%, about 40% to about 70%, orabout 50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein reduces alevel of a dehydroepiandrosterone (DHEA). In aspects of this embodiment,a therapeutic compound disclosed herein reduces a level of a DHEA by,e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90% or at least 95%. In other aspects ofthis embodiment, a therapeutic compound disclosed herein reduces a levelof a DHEA by, e.g., about 10% to about 100%, about 20% to about 100%,about 30% to about 100%, about 40% to about 100%, about 50% to about100%, about 60% to about 100%, about 70% to about 100%, about 80% toabout 100%, about 10% to about 90%, about 20% to about 90%, about 30% toabout 90%, about 40% to about 90%, about 50% to about 90%, about 60% toabout 90%, about 70% to about 90%, about 10% to about 80%, about 20% toabout 80%, about 30% to about 80%, about 40% to about 80%, about 50% toabout 80%, or about 60% to about 80%, about 10% to about 70%, about 20%to about 70%, about 30% to about 70%, about 40% to about 70%, or about50% to about 70%.

In another embodiment, a therapeutic compound disclosed herein reduces alevel of an estrogen. In aspects of this embodiment, a therapeuticcompound disclosed herein reduces a level of an estrogen by, e.g., atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90% or at least 95%. In other aspects of thisembodiment, a therapeutic compound disclosed herein reduces a level ofan estrogen by, e.g., about 10% to about 100%, about 20% to about 100%,about 30% to about 100%, about 40% to about 100%, about 50% to about100%, about 60% to about 100%, about 70% to about 100%, about 80% toabout 100%, about 10% to about 90%, about 20% to about 90%, about 30% toabout 90%, about 40% to about 90%, about 50% to about 90%, about 60% toabout 90%, about 70% to about 90%, about 10% to about 80%, about 20% toabout 80%, about 30% to about 80%, about 40% to about 80%, about 50% toabout 80%, or about 60% to about 80%, about 10% to about 70%, about 20%to about 70%, about 30% to about 70%, about 40% to about 70%, or about50% to about 70%.

In an embodiment, a therapeutic compound disclosed herein is abenzo(iso)oxazolepiperidine. Benzo(iso)oxazolepiperidines are a familyof antipsychotic drugs. In aspects of this embodiment, abenzo(iso)oxazolepiperidine may be Iloperidone{1-[4-[3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanone},ocaperidone{3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-2,9-dimethylpyrido[1,2-a]pyrimidin-4-one},paliperidone or 9-hydroxyrisperidone{3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]ethyl]-7-hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one},and risperidone{3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one}.

In some embodiment, a therapeutic compound disclosed herein is compoundI or an optionally substituted compound I.

In some embodiment, a therapeutic compound disclosed herein is compoundII or an optionally substituted compound II.

In some embodiment, a therapeutic compound disclosed herein is compoundIII or an optionally substituted compound III.

In some embodiment, a therapeutic compound disclosed herein is compoundIV or an optionally substituted compound IV.

Unless otherwise indicated, when a compound or chemical structuralfeature disclosed herein is referred to as being “optionallysubstituted,” it includes a feature that has no substituents (i.e.unsubstituted), or a feature that is “substituted,” meaning that thefeature has one or more substituents. The term “substituent” has thebroadest meaning known to one of ordinary skill in the art, and includesa moiety that replaces one or more hydrogen atoms attached to a parentcompound or structural feature. In some embodiments, a substituent maybe an ordinary organic moiety known in the art, which may have amolecular weight (e.g. the sum of the atomic masses of the atoms of thesubstituent) of 15 g/mol to 50 g/mol, 15 g/mol to 100 g/mol, 15 g/mol to150 g/mol, 15 g/mol to 200 g/mol, 15 g/mol to 300 g/mol, or 15 g/mol to500 g/mol. In some embodiments, a substituent comprises, or consists of:0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5heteroatoms, wherein each heteroatom may independently be: N, O, S, Si,F, Cl, Br, or I; provided that the substituent includes one C, N, O, S,Si, F, Cl, Br, or 1 atom. Examples of substituents include, but are notlimited to, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl,acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl,O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato,isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl,haloalkoxyl, trihalomethanesulfonyl, trihalomethanesulfonamido, amino,etc.

For convenience, the term “molecular weight” is used with respect to amoiety or part of a molecule to indicate the sum of the atomic masses ofthe atoms in the moiety or part of a molecule, even though it may not bea complete molecule.

As used herein, the term “alkyl” has the broadest meaning generallyunderstood in the art, and may include a moiety composed of carbon andhydrogen containing no double or triple bonds. Alkyl may be linearalkyl, branched alkyl, cycloalkyl, or a combination thereof, and in someembodiments, may contain from one to thirty-five carbon atoms. In someembodiments, alkyl may include C₁₋₁₀ linear alkyl, such as methyl(—CH₃), ethyl (—CH₂CH₃), n-propyl (—CH₂CH₂CH₃), n-butyl (—CH₂CH₂CH₂CH₃),n-pentyl (—CH₂CH₂CH₂CH₂CH₃), n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), etc.; C₃₋₁₀branched alkyl, such as C₃H₇ (e.g. iso-propyl), C₄H₉ (e.g. branchedbutyl isomers), C₅H₁₁ (e.g. branched pentyl isomers), C₆H₁₃ (e.g.branched hexyl isomers), C₇H₁₅ (e.g. heptyl isomers), etc.; C₃₋₁₀cycloalkyl, such as C₃H₅ (e.g. cyclopropyl), C₄H₇ (e.g. cyclobutylisomers such as cyclobutyl, methylcyclopropyl, etc.), C₅H₉ (e.g.cyclopentyl isomers such as cyclopentyl, methylcyclobutyl,dimethylcyclopropyl, etc.) C₆H₁₁ (e.g. cyclohexyl isomers), C₇H₁₃ (e.g.cycloheptyl isomers), etc.; and the like.

In an embodiment, a therapeutic compound disclosed herein is apharmaceutically-acceptable fatty acid. A fatty acid comprises acarboxylic acid with a long unbranched hydrocarbon chain which may beeither saturated or unsaturated. This arrangement confers a fatty acidwith a polar, hydrophilic end, and a nonpolar, hydrophobic end that isinsoluble in water. Most naturally occurring fatty acids have ahydrocarbon chain of an even number of carbon atoms, typically between 4and 24 carbons, and may be attached to functional groups containingoxygen, halogens, nitrogen, and sulfur. Synthetic or non-natural fattyacids may have a hydrocarbon chain of any number of carbon atoms frombetween 3 and 40 carbons. Where a double bond exists, there is thepossibility of either a cis or a trans geometric isomerism, whichsignificantly affects the molecule's molecular configuration. Cis-doublebonds cause the fatty acid chain to bend, an effect that is morepronounced the more double bonds there are in a chain. Most naturallyoccurring fatty acids are of the cis configuration, although the transform does exist in some natural and partially hydrogenated fats andoils. Examples of fatty acids include, without limitation, Capryllicacid, pelargonic acid, Capric acid, Undecylic acid, Lauric acid,Tridecylic acid, Myristic acid, Myristoleic acid, Pentadecyclic acid,Palmitic acid, Palmitoleic acid, Sapienic acid, Margaric acid, Stearicacid, Oleic acid, Elaidic acid, Vaccenic acid, Linoleic acid,Linoelaidic acid, α-Linolenic acid, γ-Linolenic acid, Stearidonic acid,Nonadecylic acid, Arachidic acid, Eicosenoic acid, Dihomo-γ-linolenicacid, Mead acid, Arachidonic acid, Eicosapentaenoic acid, Heneicosylicacid, Behenic acid, Erucic acid, Docosahexaenoic acid, Tricosylic acid,Lignoceric acid, Nervonic acid, Pentacosylic acid, Cerotic acid,Heptacosylic acid, Montanic acid, Nonacosylic acid, Melissic acid,Henatriacontylic acid, Lacceroic acid, Psyllic acid, Geddic acid,Ceroplastic acid, and Hexatriacontylic acid.

In aspects of this embodiment, a saturated or unsaturated fatty acidcomprises, e.g., at least 8, at least 10, at least 12, at least 14, atleast 16, at least 18, at least 20, at least 22, at least 24, at least26, at least 28, or at least 30 carbon atoms, In other aspects of thisembodiment, a saturated or unsaturated fatty acid comprises, e.g.,between 4 and 24 carbon atoms, between 6 and 24 carbon atoms, between 8and 24 carbon atoms, between 10 and 24 carbon atoms, between 12 and 24carbon atoms, between 14 and 24 carbon atoms, or between 16 and 24carbon atoms, between 4 and 22 carbon atoms, between 6 and 22 carbonatoms, between 8 and 22 carbon atoms, between 10 and 22 carbon atoms,between 12 and 22 carbon atoms, between 14 and 22 carbon atoms, orbetween 16 and 22 carbon atoms, between 4 and 20 carbon atoms, between 6and 20 carbon atoms, between 8 and 20 carbon atoms, between 10 and 20carbon atoms, between 12 and 20 carbon atoms, between 14 and 20 carbonatoms, or between 16 and 20 carbon atoms. If unsaturated, the fatty acidmay have, e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or more,or 6 or more double bonds.

In another embodiment, an adjuvant may comprise one kind ofpharmaceutically-acceptable fatty acid. In another embodiment, anadjuvant may comprise a plurality of differentpharmaceutically-acceptable fatty acids. In aspects of this embodiment,an adjuvant may comprise, e.g., two or more different fatty acids, threeor more different fatty acids, four or more different fatty acids, fiveor more different fatty acids, or six or more different fatty acids.

A pharmaceutically-acceptable fatty acid useful in the pharmaceuticalcompositions disclosed herein may be a pharmaceutically-acceptable omegafatty acid. Non-limiting examples of an omega fatty acid include anomega-3 fatty acid, an omega-6 fatty acid, an omega-7 fatty acid, anomega-9 fatty acid. Omega-3 fatty acids (also known as n-3 fatty acidsor ω-3 fatty acids) are a family of essential unsaturated fatty acidsthat have in common a final carbon-carbon double bond in the n-3position, that is, the third bond, counting from the methyl end of thefatty acid. The omega-3 fatty acids are “essential” fatty acids becausethey are vital for normal metabolism and cannot be synthesized by thehuman body. An omega-3 fatty acid includes, without limitation,Hexadecatrienoic acid (16:3), α-Linolenic acid (18:3), Stearidonic acid(18:4), Eicosatrienoic acid (20:3), Eicosatetraenoic acid (20:4),Eicosapentaenoic acid (20:5), Heneicosapentaenoic acid (21:5),Docosapentaenoic acid (Clupanodonic acid) (22:5), Docosahexaenoic acid(22:6), Tetracosapentaenoic acid (24:5), Tetracosahexaenoic acid(Nisinic acid) (24:6).

Omega-6 fatty acids (also known as n-6 fatty acids or ω-6 fatty acids)are a family of unsaturated fatty acids that have in common a finalcarbon-carbon double bond in the n-6 position, that is, the sixth bond,counting from the methyl end of the fatty acid. An omega-6 fatty acidincludes, without limitation, Linoleic acid (18:2), γ-linolenic acid(18:3), Calendic acid (18:3), Eicosadienoic acid (20:2),Dihomo-γ-linolenic acid (20:3), Arachidonic acid (20:4), Docosadienoicacid (22:2), Adrenic acid (22:4), Docosapentaenoic acid (22:5),Tetracosatetraenoic acid (24:4), and Tetracosapentaenoic acid (24:5).

Omega-7 fatty acids (also known as n-7 fatty acids or ω-7 fatty acids)are a family of unsaturated fatty acids that have in common a finalcarbon-carbon double bond in the n-7 position, that is, the seventhbond, counting from the methyl end of the fatty acid. An omega-7 fattyacid includes, without limitation, 5-Dodecenoic acid (12:1),7-Tetradecenoic acid (14:1), 9-Hexadecenoic acid (Palmitoleic acid)(16:1), 11-Decenoic acid (Vaccenic acid) (18:1), 9Z,11E conjugatedLinoleic acid (Rumenic acid)(18:2), 13-Eicosenoic acid (Paullinic acid)(20:1), 15-Docosenoic acid (22:1), and 17-Tetracosenoic acid (24:1).

Omega-9 fatty acids (also known as n-9 fatty acids or ω-9 fatty acids)are a family of unsaturated fatty acids that have in common a finalcarbon-carbon double bond in the n-9 position, that is, the ninth bond,counting from the methyl end of the fatty acid. An omega-9 fatty acidincludes, without limitation, Oleic acid (18:1), Elaidic acid (18:1),Eicosenoic acid (20:1), Mead acid (20:3), Erucic acid (22:1), Nervonicacid (24:1), and Ricinoleic acid.

A pharmaceutically-acceptable fatty acid useful in the pharmaceuticalcompositions disclosed herein may be a pharmaceutically-acceptableconjugated linoleic acid (CLA). Conjugated linoleic acid (CLA) refers toa group of at least 28 positional and geometric isomers of the omega-6essential fatty acid linoleic acid (cis-9, cis-12, octadecadienoicacid). The double bonds of CLAs are conjugated, with only one singlebond between them. Virtually all cis- and trans-isomeric combinations ofCLA have been identified. A CLA includes, without limitation, cis-9,trans-11, octadecadienoic acid (c-9, t-11 CLA), cis-9, cis-11,octadecadienoic acid (c-9, c-11 CLA), trans-9, trans-11, octadecadienoicacid (t-9, t-11 CLA), and trans-9, cis-11, octadecadienoic acid (t-9,c-11 CLA), and any combination thereof.

In an embodiment, a therapeutic compound disclosed herein is a 5αreductase inhibitor. The enzyme 5α-reductase is involved in theconversion of testosterone to the active form dihydrotestosterone (DHT)by reducing the Δ4,5 double-bond. In benign prostatic hyperplasia,dihydrotestosterone acts as a potent cellular androgen and promotesprostate growth; therefore, inhibiting the enzyme reduces the excessiveprostate growth. In alopecia, male-pattern baldness is one of theeffects of androgenic receptor activation. Thus, reducing the levels ofdihydrotestosterone reduces alopecia. These inhibitors decrease thelevels of available 5α-reductase prior to testosterone's binding withthe enzyme, thus reducing levels of dihydrotestosterone that derivesfrom such a bond. A 5α reductase inhibitor include, without limitation,Alfatradiol, Bexlosteride, Dutasteride, Epristeride, Finasteride,Isotretinoin, Lapisteride, Turosteride

In an embodiment, a therapeutic compound disclosed herein is achemotherapeutic agent or an anti-proliferative agent. Achemotherapeutic agent or other anti-proliferative agent include,without limitation, alkylating agents, such as, for example,cyclophosphamide, lomustine, busulfan procarbazine, ifosfamide,altretamine, melphalan, estramustine phosphate, hexamethylmelamine,mechlorethamine, thiotepa, streptozocin, chlorambucil, temozolomide,dacarbazine, semustine, or carmustine; platinum agents, such as, forexample, cisplatin, carboplatinum, oxaliplatin, ZD-0473 (AnorMED),spiroplatinum, lobaplatin (Aeterna), carboxyphthalatoplatinum,satraplatin (Johnson Matthey), tetraplatin BBR-3464, (Hoffmann-LaRoche), ormiplatin, SM-11355 (Sumitomo), iproplatin, or AP-5280(Access); antimetabolites, such as, for example, azacytidine, tomudex,gemcitabine, trimetrexate, capecitabine, deoxycoformycin,5-fluorouracil, fludarabine, floxuridine, pentostatin,2-chlorodeoxyadenosine, raltitrexed, 6-mercaptopurine, hydroxyurea,6-thioguanine, decitabine (SuperGen), cytarabin, clofarabine(Bioenvision), 2-fluorodeoxy cytidine, irofulven (MGI Pharma),methotrexate, DMDC (Hoffmann-La Roche), idatrexate, or ethynylcytidine(Taiho); topoisomerase inhibitors, such as, for example, amsacrine,rubitecan (SuperGen), epirubicin, exatecan mesylate (Daiichi),etoposide, quinamed (ChemGenex), teniposide, mitoxantrone, gimatecan(Sigma-Tau), irinotecan (CPT-11), diflomotecan (Beaufour-Ipsen),7-ethyl-10-hydroxy-camptothecin, TAS-103 (Taiho), topotecan,elsamitrucin (Spectrum), dexrazoxanet (TopoTarget), J-107088 (Merck &Co), pixantrone (Novuspharma), BNP-1350 (BioNumerik), rebeccamycinanalogue (Exelixis), CKD-602 (Chong Kun Dang), BBR-3576 (Novuspharma),or KW-2170 (Kyowa Hakko); antitumor antibiotics, such as, for example,dactinomycin (actinomycin D), amonafide, doxorubicin (adriamycin),azonafide, deoxyrubicin, anthrapyrazole, valrubicin, oxantrazole,daunorubicin (daunomycin), losoxantrone, epirubicin, bleomycin, sulfate(blenoxane), therarubicin, bleomycinic acid, idarubicin, bleomycin A,rubidazone, bleomycin B, plicamycin, mitomycin C, porfiromycin,MEN-10755 (Menarini), cyanomorpholinodoxorubicin, GPX-100 (GemPharmaceuticals), or mitoxantrone (novantrone), antimitotic agents, suchas, for example, paclitaxel, SB 408075 (GlaxoSmithKline), docetaxel,E7010 (Abbott), colchicines, PG-TXL (Cell Therapeutics), vinblastine,IDN 5109 (Bayer), vincristine A, 105972 (Abbott), vinorelbine, A 204197(Abbott), vindesine, LU 223651 (BASF), dolastatin 10 (NCI), D 24851(ASTAMedica), rhizoxin (Fujisawa), ER-86526 (Eisai), mivobulin(Warner-Lambert), combretastatin A4 (BMS), cemadotin (BASF),isohomohalichondrin-B (PharmaMar), RPR 109881A (Aventis), ZD 6126(AstraZeneca), TXD 258 (Aventis), PEG-paclitaxel (Enzon,) epothilone B(Novartis), AZ10992 (Asahi), T 900607 (Tularik), IDN-5109 (Indena), T138067 (Tularik), AVLB (Prescient NeuroPharma), cryptophycin 52 (EliLilly), azaepothilone B (BMS), vinflunine (Fabre), BNP-7787(BioNumerik), auristatin PE (Teikoku Hormone), CA-4 prodrug (OXiGENE),BMS 247550 (BMS), dolastatin-10 (NIH), BMS 184476 (BMS), CA-4 (OXiGENE),BMS 188797 (BMS), or taxoprexin (Protarga); aromatase inhibitors, suchas, for example, aminoglutethimide, exemestane, letrozole, atamestane(BioMedicines), anastrazole, YM-511 (Yamanouchi), or formestane;thymidylate synthase inhibitors, such as, for example, pemetrexed (EliLilly), nolatrexed (Eximias), ZD-9331 (BTG), or CoFactor™ (BioKeys); DNAantagonists, such as, for example, trabectedin (PharmaMar), mafosfamide(Baxter International), glufosfamide (Baxter International), apaziquone(Spectrum Pharmaceuticals), albumin+.sup.32P (Isotope Solutions), 06benzyl guanine (Paligent), thymectacin (NewBiotics), or edotreotide(Novartis); farnesyltransferase inhibitors, such as, for example,arglabin (NuOncology Labs), tipifarnib (Johnson & Johnson), lonafarnib(Schering-Plough), perillyl alcohol (DOR BioPharma), or BAY-43-9006(Bayer); Pump inhibitors, such as, for example, CBT-1 (CBA Pharma),zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodardicitrate (Vertex), or MS-209 (Schering AG); Histone acetyltransferaseinhibitors, such as, for example, tacedinaline (Pfizer),pivaloyloxymethyl butyrate (Titan), SAHA (Aton Pharma), depsipeptide(Fujisawa), or MS-275 (Schering AG); Metalloproteinase inhibitors, suchas, for example, Neovastat (Aeterna Laboratories), CMT-3 (CollaGenex),marimastat (British Biotech), or BMS-275291 (Celltech); ribonucleosidereductase inhibitors, such as, for example, gallium maltolate (Titan),tezacitabine (Aventis), triapine (Vion), or didox (Molecules forHealth); TNF alpha agonists/antagonists, such as, for example, virulizin(Lorus Therapeutics), revimid (Celgene), CDC-394 (Celgene), entanercept(Immunex Corp.), infliximab (Centocor, Inc.), or adalimumab (AbbottLaboratories); endothelin A receptor antagonists, such as, for example,atrasentan (Abbott) YM-598 (Yamanouchi) or ZD-4054 (AstraZeneca);retinoic acid receptor agonists, such as, for example, fenretinide(Johnson & Johnson) alitretinoin (Ligand) or LGD-1550 (Ligand);immuno-modulators, such as, for example, interferon dexosome therapy(Anosys), oncophage (Antigenics), pentrix (Australian CancerTechnology), GMK (Progenics), ISF-154 (Tragen), adenocarcinoma vaccine(Biomira), cancer vaccine (Intercell), CTP-37 (AVI BioPharma), norelin(Biostar), IRX-2 (Immuno-Rx), BLP-25 (Biomira), PEP-005 (PeplinBiotech), MGV (Progenics), synchrovax vaccines (CTL Immuno),beta-alethine (Dovetail), melanoma vaccine (CTL Immuno), CLL therapy(Vasogen), or p21 RAS vaccine (GemVax); hormonal and antihormonalagents, such as, for example, estrogens, prednisone, conjugatedestrogens, methylprednisolone, ethinyl estradiol, prednisolone,chlortrianisen, aminoglutethimide, idenestrol, leuprolide,hydroxyprogesterone caproate, goserelin, medroxyprogesterone,leuporelin, testosterone, bicalutamide, testosterone propionate,fluoxymesterone, flutamide, methyltestosterone, octreotide,diethylstilbestrol, nilutamide, megestrol, mitotane, tamoxifen, P-04(Novogen), toremofine, 2-methoxyestradiol (EntreMed), dexamethasone, orarzoxifene (Eli Lilly); photodynamic agents, such as, for example,talaporfin (Light Sciences), Pd-bacteriopheophorbide (Yeda), Theralux(Theratechnologies), lutetium texaphyrin (Pharmacyclics), motexafingadolinium (Pharmacyclics), or hypericin; and tyrosine kinaseinhibitors, such as, for example, imatinib (Novartis), kahalide F(PharmaMar), leflunomide (Sugen/Pharmacia), CEP-701 (Cephalon), ZD1839(AstraZeneca), CEP-751 (Cephalon), erlotinib (Oncogene Science), MLN518(Millenium), canertinib (Pfizer), PKC412 (Novartis), squalamine(Genaera), phenoxodiol, SU5416 (Pharmacia), trastuzumab (Genentech),SU6668 (Pharmacia), C225 (ImClone), ZD4190 (AstraZeneca), rhu-Mab(Genentech), ZD6474 (AstraZeneca), MDX-H210 (Medarex), vatalanib(Novartis), 2C4 (Genentech), PK1166 (Novartis), MDX-447 (Medarex),GW2016 (GlaxoSmithKline), ABX-EGF (Abgenix), EKB-509 (Wyeth), IMC-1C11(ImClone), or EKB-569 (Wyeth).

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition may also be present in the compositions disclosed herein.As used herein, additional therapeutic agents that are normallyadministered to treat a particular disease, or condition, are known as“appropriate for the disease, or condition, being treated”.

In an embodiment, a pharmaceutical composition comprises abenzo(iso)oxazolepiperidine and a fatty acid. In an aspect of thisembodiment, a pharmaceutical composition comprises abenzo(iso)oxazolepiperidine and an Omega-3 fatty acid. In another aspectof this embodiment, a pharmaceutical composition comprises abenzo(iso)oxazolepiperidine and an Omega-6 fatty acid. In yet anotheraspect of this embodiment, a pharmaceutical composition comprises abenzo(iso)oxazolepiperidine and an Omega-7 fatty acid. In still anotheraspect of this embodiment, a pharmaceutical composition comprises abenzo(iso)oxazolepiperidine and an Omega-9 fatty acid. In other aspects,a pharmaceutical composition comprises Risperidone and an Omega-3 fattyacid, an Omega-6 fatty acid, an Omega-7 fatty acid, an Omega-9 fattyacid, or any combination thereof. In yet other aspects, a pharmaceuticalcomposition comprises Risperidone and α-Linolenic acid, Arachidonicacid, Docosahexaenoic acid, Rumenic acid, or any combination thereof.

A pharmaceutical composition disclosed herein may optionally include apharmaceutically-acceptable carrier that facilitates processing of anactive ingredient into pharmaceutically-acceptable compositions. As usedherein, the term “pharmacologically-acceptable carrier” is synonymouswith “pharmacological carrier” and means any carrier that hassubstantially no long term or permanent detrimental effect whenadministered and encompasses terms such as “pharmacologically acceptablevehicle, stabilizer, diluent, additive, auxiliary or excipient.” Such acarrier generally is mixed with an active compound or permitted todilute or enclose the active compound and can be a solid, semi-solid, orliquid agent. It is understood that the active ingredients can besoluble or can be delivered as a suspension in the desired carrier ordiluent. Any of a variety of pharmaceutically acceptable carriers can beused including, without limitation, aqueous media such as, e.g., water,saline, glycine, hyaluronic acid and the like; solid carriers such as,e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin,talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like;solvents; dispersion media; coatings; antibacterial and antifungalagents; isotonic and absorption delaying agents; or any other inactiveingredient. Selection of a pharmacologically acceptable carrier candepend on the mode of administration. Except insofar as anypharmacologically acceptable carrier is incompatible with the activeingredient, its use in pharmaceutically acceptable compositions iscontemplated. Non-limiting examples of specific uses of suchpharmaceutical carriers can be found in Pharmaceutical Dosage Forms andDrug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams& Wilkins Publishers, 7th ed. 1999); REMINGTON: THE SCIENCE AND PRACTICEOF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins,20th ed. 2000); Goodman & Gilman's The Pharmacological Basis ofTherapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional,10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C.Rowe et al., APhA Publications, 4th edition 2003). These protocols areroutine procedures and any modifications are well within the scope ofone skilled in the art and from the teaching herein.

A pharmaceutical composition disclosed herein can optionally include,without limitation, other pharmaceutically acceptable components (orpharmaceutical components), including, without limitation, buffers,preservatives, tonicity adjusters, salts, antioxidants, osmolalityadjusting agents, physiological substances, pharmacological substances,bulking agents, emulsifying agents, wetting agents, flavoring agents,coloring agents, and the like. Various buffers and means for adjustingpH can be used to prepare a pharmaceutical composition disclosed herein,provided that the resulting preparation is pharmaceutically acceptable.Such buffers include, without limitation, acetate buffers, citratebuffers, phosphate buffers, neutral buffered saline, phosphate bufferedsaline and borate buffers. It is understood that acids or bases can beused to adjust the pH of a composition as needed. Pharmaceuticallyacceptable antioxidants include, without limitation, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene. Useful preservativesinclude, without limitation, benzalkonium chloride, chlorobutanol,thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilizedoxy chloro composition and chelants, such as, e.g., DTPA orDTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity adjustorsuseful in a pharmaceutical composition include, without limitation,salts such as, e.g., sodium chloride, potassium chloride, mannitol orglycerin and other pharmaceutically acceptable tonicity adjustor. Thepharmaceutical composition may be provided as a salt and can be formedwith many acids, including but not limited to, hydrochloric, sulfuric,acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be moresoluble in aqueous or other protonic solvents than are the correspondingfree base forms. It is understood that these and other substances knownin the art of pharmacology can be included in a pharmaceuticalcomposition.

A therapeutic compound disclosed herein, or a composition comprisingsuch a therapeutic compound, may be formulated for either local orsystemic delivery using topical, enteral or parenteral routes ofadministration. Additionally, a therapeutic compound disclosed hereinmay be formulated by itself in a pharmaceutical composition, or may beformulated together with one or more other therapeutic compoundsdisclosed herein in a single pharmaceutical composition.

A therapeutic compound disclosed herein, or a composition comprisingsuch a therapeutic compound, may be made into an inhaled formulation.Inhaled formulations suitable for enteral or parenteral administrationinclude, without limitation, aerosols, dry powders. A therapeuticcompound or composition disclosed herein intended for suchadministration may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions.

In such inhaled dosage forms, the therapeutic compound may be preparedfor delivery as an aerosol in a liquid propellant for use in apressurised (PDI) or other metered dose inhaler (MDI). Propellantssuitable for use in a PDI or MDI include, without limitation, CFC-12,HFA-134a, HFA-227, HCFC-22 (difluorochloromethane), HFA-152(difluoroethane and isobutane). A therapeutic compound may also bedelivered using a nebulisers or other aerosol delivery system. Atherapeutic compound may be prepared for delivery as a dry powder foruse in a dry powder inhaler (DPI). A dry powder for use in the inhalerswill usually have a mass median aerodynamic diameter of less than 30 pm,preferably less than 20 pm and more preferably less than 10 pm.Microparticles having aerodynamic diameters in the range of about 5 pmto about 0.5 pm will generally be deposited in the respiratorybronchioles, whereas smaller particles, having aerodynamic diameters inthe range of about 2 pm to about 0.05 pm, are likely to be deposited inthe alveoli. A DPI may be a passive delivery mechanism, which relies onthe individual's inspiration to introduce the particles into the lungs,or an active delivery mechanism, requiring a mechanism for deliveringthe powder to the individual. In inhalatory formulations, atherapeutically effective amount of a therapeutic compound disclosedherein for an inhaled formulation may be between about 0.0001% (w/v) toabout 60% (w/v), about 0.001% (w/v) to about 40.0% (w/v), or about 0.01%(w/v) to about 20.0% (w/v). In inhalatory formulations, atherapeutically effective amount of a therapeutic compound disclosedherein for an inhaled formulation may also be between about 0.0001%(w/w) to about 60% (w/w), about 0.001% (w/w) to about 40.0% (w/w), orabout 0.01% (w/w) to about 20.0% (w/w).

A therapeutic compound disclosed herein, or a composition comprisingsuch a therapeutic compound, may be made into a solid formulation. Solidformulations suitable for enteral or parenteral administration include,without limitation, capsules, tablets, pills, troches, lozenges, powdersand granules suitable for inhalation or for reconstitution into sterileinjectable solutions or dispersions. A therapeutic compound orcomposition disclosed herein intended for such administration may beprepared according to any method known to the art for the manufacture ofpharmaceutical compositions. In such solid dosage forms, the therapeuticcompound may be admixed with (a) at least one inert customary excipient(or carrier), such as, e.g., sodium citrate or dicalcium phosphate or(b) fillers or extenders, as for example, starch, lactose, sucrose,glucose, mannitol, isomalt, and silicic acid, (c) binders, such as,e.g., carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose and acacia, (d) humectants, such as, e.g., glycerol, (e)disintegrating agents, such as, e.g., agar-agar, calcium carbonate, cornstarch, potato starch, tapioca starch, alginic acid, certain complexsilicates and sodium carbonate, (f) solution retarders, such as, e.g.,paraffin, (g) absorption accelerators, such as, e.g., quaternaryammonium compounds, (h) wetting agents, such as, e.g., cetyl alcohol andglycerol monostearate, (i) adsorbents, such as, e.g., kaolin andbentonite, (j) lubricants, such as, e.g., talc, stearic acid, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate or mixtures thereof, and (k) buffering agents. The tablets maybe uncoated or they may be coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate maybe employed. In solid formulations, a therapeutically effective amountof a therapeutic compound disclosed herein typically may be betweenabout 0.0001% (w/w) to about 60% (w/w), about 0.001% (w/w) to about40.0% (w/w), or about 0.01% (w/w) to about 20.0% (w/w).

A therapeutic compound disclosed herein, or a composition comprisingsuch a therapeutic compound, may be made into a semi-solid formulation.Semi-solid formulations suitable for topical administration include,without limitation, ointments, creams, salves, and gels. A therapeuticcompound or composition disclosed herein intended for suchadministration may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions. In semi-solidformulations, a therapeutically effective amount of a therapeuticcompound disclosed herein typically may be between about 0.0001% (w/v)to about 60% (w/v), about 0.001% (w/v) to about 40.0% (w/v), or about0.01% (w/v) to about 20.0% (w/v). In semi-solid formulations, atherapeutically effective amount of a therapeutic compound disclosedherein typically may also be between about 0.0001% (w/w) to about 60%(w/w), about 0.001% (w/w) to about 40.0% (w/w), or about 0.01% (w/w) toabout 20.0% (w/w).

A therapeutic compound disclosed herein, or a composition comprisingsuch a therapeutic compound, may be made into a liquid formulation.Liquid formulations suitable for enteral or parenteral administrationinclude, without limitation, solutions, syrups, elixirs, dispersions,emulsions, and suspensions. A therapeutic compound or compositiondisclosed herein intended for such administration may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions. In such liquid dosage forms, a therapeuticcompound or composition disclosed herein may be admixed with (a)suitable aqueous and nonaqueous carriers, (b) diluents, (c) solvents,such as, e.g., water, ethanol, propylene glycol, polyethyleneglycol,glycerol, vegetable oils, such as, e.g., rapeseed oil and olive oil, andinjectable organic esters such as ethyl oleate; and/or fluidity agents,such as, e.g., surfactants or coating agents like lecithin. In the caseof dispersions and suspensions, fluidity can also be controlled bymaintaining a particular particle size. In liquid formulations, atherapeutically effective amount of a therapeutic compound disclosedherein typically may be between about 0.0001% (w/v) to about 60% (w/v),about 0.001% (w/v) to about 40.0% (w/v), or about 0.01% (w/v) to about20.0% (w/v).

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring agents, and coloringagents.

Liquid suspensions may be formulated by suspending a therapeuticcompound disclosed herein in admixture with excipients suitable for themanufacture of aqueous suspensions. Such excipients are suspendingagents, for example sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, pectin, polyvinylpyrrolidone, polyvinyl alcohol, natural gum, agar, gum tragacanth andgum acacia; dispersing or wetting agents may be a naturally occurringphosphatide, for example lecithin, or condensation products of analkylene oxide with fatty acids, for example polyoxyethylene stearate,or condensation products of ethylene oxide with long-chain aliphaticalcohols, for example heptadecaethyleneoxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acids,for example polyoxyethylene sorbitan monooleate.

Oily suspensions may be formulated by suspending a therapeutic compounddisclosed herein in admixture with (a) vegetable oils, such as, e.g.,almond oil, arachis oil, avocado oil, canola oil, castor oil, coconutoil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil,linseed oil, olive oil, palm oil, peanut oil, rapeseed oil, rice branoil, safflower oil, sesame oil, soybean oil, soya oil, sunflower oil,walnut oil, wheat germ oil, or a combination thereof, (b) a saturatedfatty acid, an unsaturated fatty acid, or a combination thereof, suchas, e.g., palmitic acid, stearic acid, oleic acid, linoleic acid,linolenic acid, or a combination thereof, (c) mineral oil such as, e.g.,liquid paraffin, (d) surfactants or detergents. The oily suspensions maycontain a thickening agent, for example beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the combined therapeuticcompounds in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives.

A therapeutic compound disclosed herein may be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil asdisclosed herein or a mineral oil as disclosed herein or mixturesthereof. Suitable emulsifying agents may be naturally occurring gums,such as, e.g., gum acacia or gum tragacanth, naturally occurringphosphatides, for example soya bean, lecithin, and esters or partialesters derived from fatty acids and hexitol anhydrides, for examplesorbitan monooleate and condensation products of the said partial esterswith ethylene oxide, for example polyoxyethylene sorbitan monooleate.

A therapeutic compound disclosed herein, or a composition comprisingsuch a therapeutic compound, may also be incorporated into a drugdelivery platform in order to achieve a controlled release profile overtime. Such a drug delivery platform comprises a therapeutic compounddisclosed herein dispersed within a polymer matrix, typically abiodegradable, bioerodible, and/or bioresorbable polymer matrix. As usedherein, the term “polymer” refers to synthetic homo- or copolymers,naturally occurring homo- or copolymers, as well as syntheticmodifications or derivatives thereof having a linear, branched or starstructure. Copolymers can be arranged in any form, such as, e.g.,random, block, segmented, tapered blocks, graft, or triblock. Polymersare generally condensation polymers. Polymers can be further modified toenhance their mechanical or degradation properties by introducingcross-linking agents or changing the hydrophobicity of the sideresidues. If crosslinked, polymers are usually less than 5% crosslinked,usually less than 1% crosslinked.

Suitable polymers include, without limitation, alginates, aliphaticpolyesters, polyalkylene oxalates, polyamides, polyamidoesters,polyanhydrides, polycarbonates, polyesters, polyethylene glycol,polyhydroxyaliphatic carboxylic acids, polyorthoesters, polyoxaesters,polypeptides, polyphosphazenes, polysaccharides, and polyurethanes. Thepolymer usually comprises at least about 10% (w/w), at least about 20%(w/w), at least about 30% (w/w), at least about 40% (w/w), at leastabout 50% (w/w), at least about 60% (w/w), at least about 70% (w/w), atleast about 80% (w/w), or at least about 90% (w/w) of the drug deliveryplatform. Examples of biodegradable, bioerodible, and/or bioresorbablepolymers and methods useful to make a drug delivery platform aredescribed in, e.g., Drost, et. al., Controlled Release Formulation, U.S.Pat. No. 4,756,911; Smith, et. al., Sustained Release Drug DeliveryDevices, U.S. Pat. No. 5,378,475; Wong and Kochinke, Formulation forControlled Release of Drugs by Combining Hyrophilic and HydrophobicAgents, U.S. Pat. No. 7,048,946; Hughes, et. al., Compositions andMethods for Localized Therapy of the Eye, U.S. Patent Publication2005/0181017; Hughes, Hypotensive Lipid-Containing BiodegradableIntraocular Implants and Related Methods, U.S. Patent Publication2005/0244464; Altman, et al., Silk Fibroin Hydrogels and Uses Thereof,U.S. Patent Publication 2011/0008437; each of which is incorporated byreference in its entirety.

In aspects of this embodiment, a polymer composing the matrix is apolypeptide such as, e.g., silk fibroin, keratin, or collagen. In otheraspects of this embodiment, a polymer composing the matrix is apolysaccharide such as, e.g., cellulose, agarose, elastin, chitosan,chitin, or a glycosaminoglycan like chondroitin sulfate, dermatansulfate, keratan sulfate, or hyaluronic acid. In yet other aspects ofthis embodiment, a polymer composing the matrix is a polyester such as,e.g., D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid,caprolactone, and combinations thereof.

One of ordinary skill in the art appreciates that the selection of asuitable polymer for forming a suitable disclosed drug delivery platformdepends on several factors. The more relevant factors in the selectionof the appropriate polymer(s), include, without limitation,compatibility of polymer with drug, desired release kinetics of drug,desired biodegradation kinetics of platform at implantation site,desired bioerodible kinetics of platform at implantation site, desiredbioresorbable kinetics of platform at implantation site, in vivomechanical performance of platform, processing temperatures,biocompatibility of platform, and patient tolerance. Other relevantfactors that, to some extent, dictate the in vitro and in vivo behaviorof the polymer include the chemical composition, spatial distribution ofthe constituents, the molecular weight of the polymer and the degree ofcrystallinity.

A drug delivery platform includes both a sustained release drug deliveryplatform and an extended release drug delivery platform. As used herein,the term “sustained release” refers to the release of a therapeuticcompound disclosed herein over a period of about seven days or more. Asused herein, the term “extended release” refers to the release of atherapeutic compound disclosed herein over a period of time of less thanabout seven days.

In aspects of this embodiment, a sustained release drug deliveryplatform releases a therapeutic compound disclosed herein withsubstantially zero order release kinetics over a period of, e.g., about7 days after administration, about 15 days after administration, about30 days after administration, about 45 days after administration, about60 days after administration, about 75 days after administration, orabout 90 days after administration. In other aspects of this embodiment,a sustained release drug delivery platform releases a therapeuticcompound disclosed herein with substantially zero order release kineticsover a period of, e.g., at least 7 days after administration, at least15 days after administration, at least 30 days after administration, atleast 45 days after administration, at least 60 days afteradministration, at least 75 days after administration, or at least 90days after administration.

In aspects of this embodiment, a sustained release drug deliveryplatform releases a therapeutic compound disclosed herein withsubstantially first order release kinetics over a period of, e.g., about7 days after administration, about 15 days after administration, about30 days after administration, about 45 days after administration, about60 days after administration, about 75 days after administration, orabout 90 days after administration. In other aspects of this embodiment,a sustained release drug delivery platform releases a therapeuticcompound disclosed herein with substantially first order releasekinetics over a period of, e.g., at least 7 days after administration,at least 15 days after administration, at least 30 days afteradministration, at least 45 days after administration, at least 60 daysafter administration, at least 75 days after administration, or at least90 days after administration.

In aspects of this embodiment, a drug delivery platform releases atherapeutic compound disclosed herein with substantially zero orderrelease kinetics over a period of, e.g., about 1 day afteradministration, about 2 days after administration, about 3 days afteradministration, about 4 days after administration, about 5 days afteradministration, or about 6 days after administration. In other aspectsof this embodiment, a drug delivery platform releases a therapeuticcompound disclosed herein with substantially zero order release kineticsover a period of, e.g., at most 1 day after administration, at most 2days after administration, at most 3 days after administration, at most4 days after administration, at most 5 days after administration, or atmost 6 days after administration.

In aspects of this embodiment, a drug delivery platform releases atherapeutic compound disclosed herein with substantially first orderrelease kinetics over a period of, e.g., about 1 day afteradministration, about 2 days after administration, about 3 days afteradministration, about 4 days after administration, about 5 days afteradministration, or about 6 days after administration. In other aspectsof this embodiment, a drug delivery platform releases a therapeuticcompound disclosed herein with substantially first order releasekinetics over a period of, e.g., at most 1 day after administration, atmost 2 days after administration, at most 3 days after administration,at most 4 days after administration, at most 5 days afteradministration, or at most 6 days after administration.

Aspects of the present specification disclose, in part, a method oftreating an individual with a disorder associated with androgenproduction. In one embodiment, the method comprises the step ofadministering to an individual in need thereof a pharmaceuticalcomposition disclosed herein, wherein administration reduces a symptomof a disorder associated with androgen production, thereby treating theindividual. In aspects of this embodiment, a disorder associated withandrogen production includes, without limitation, a disorder associatedwith steroid hydroxy-dehydrogenase activity, a disorder associated withHSD17B activity, and a disorder associated with HSD17B10 activity.

In one embodiment, a disorder associated with androgen production may bea hormone-sensitive or hormone-dependent disorder, such as, e.g., ahormone-sensitive or hormone-dependent cancer, a hormone-sensitive orhormone-dependent non-cancerous cell proliferation disorder, or ahormone-sensitive or hormone-dependent non-cell proliferation disorder.Examples of a hormone-sensitive or hormone-dependent cancer include,without limitation, a prostate cancer, a testicular cancer, a breastcancer, an endometrial cancer, an ovarian cancer, a lung cancer, athyroid cancer, and a bone cancer. Examples of a hormone-sensitive orhormone-dependent non-cancerous cell proliferation disorder include,without limitation, a uterine fibroid, a fibrocystic breast disease, anovarian cyst, a polycystic ovary syndrome, and prostate enlargement likebenign prostatic hyperplasia (BPH). Examples of a hormone-sensitive orhormone-dependent non-cell proliferation disorder include, withoutlimitation, an acne vulgaris, a seborrhea, a female hirsutism, abnormaluterine bleeding, amenorrhoea, premenstrual syndrome (PMS),endometriosis, adenomyosis, and an alopecia.

Aspects of the present specification disclose, in part, treating anindividual suffering from a disorder associated with androgenproduction. As used herein, the term “treating,” refers to reducing oreliminating in an individual a clinical symptom of a disorder associatedwith androgen production; or delaying or preventing in an individual theonset of a clinical symptom of a disorder associated with androgenproduction. For example, the term “treating” can mean reducing a symptomof a disorder associated with androgen production by, e.g., at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90% at least95%, or at least 100%. As another example, the term “treating” can meancontrolling a symptom of a disorder associated with androgen productionsuch as, e.g., reducing the number of symptoms per given time periodand/or the severity of a symptom. The actual symptoms associated with adisorder associated with androgen production are well known and can bedetermined by a person of ordinary skill in the art by taking intoaccount factors, including, without limitation, the location of thedisorder associated with androgen production, the cause of the disorderassociated with androgen production, the severity of the disorderassociated with androgen production, and/or the cells, tissue or organaffected by the disorder associated with androgen production. Those ofskill in the art will know the appropriate symptoms or indicatorsassociated with a specific type of a disorder associated with androgenproduction and will know how to determine if an individual is acandidate for treatment as disclosed herein.

The actual symptoms of a disorder associated with androgen productionare well known and can be determined by a person of ordinary skill inthe art by taking into account factors, including, without limitation,the location of the disorder associated with androgen production, thecause of the disorder associated with androgen production, the severityof the disorder associated with androgen production, the cell, tissueand/or organ affected by the disorder associated with androgenproduction. For example, a disorder associated with androgen productionmay cause one or more of the following symptoms: urinary hesitancy,frequent urination, dysuria (painful urination), increased risk ofurinary tract infections, and urinary retention, abnormal bleeding,inflammation, abnormal hair growth, pain, sexual dysfunction.

Aspects of the present invention provide, in part, reducing a symptomassociated with a hormone-sensitive or hormone-dependent cancer. Atreatment using the disclosed therapeutic compounds and compositionsdisclosed herein may decrease the growth rate of tumor cells, decreasethe cell division rate of tumor cells, decrease the extent of invasionof tumor cells into adjacent tissue or organs, decrease the extent ofmetastasis, decrease angiogenesis, increase apoptosis, increase tumorcell death, increase tumor cell necrosis, or any combination thereof

Aspects of the present invention provide, in part, reducing a symptomassociated with a hormone-sensitive or hormone-dependent non-cancerouscell proliferation disorder. A treatment using the disclosed therapeuticcompounds and compositions disclosed herein may decrease hyperplasia,decrease the growth rate of hyperproliferating cells, decrease the celldivision rate of hyperproliferating cells, decrease the extent to whichhyperproliferating cells becomes cancerous, decrease angiogenesis,decrease nodule formation, decrease cyst formation, increase apoptosis,increase tumor cell death and/or increase tumor cell necrosis, or anycombination thereof.

Aspects of the present invention provide, in part, reducing a symptomassociated with a hormone-sensitive or hormone-dependent non-cancerouscell proliferation disorder. A treatment using the disclosed therapeuticcompounds and compositions disclosed herein may improve at least onehair attribute including, without limitation, increase hair length,increase hair thickness, increase new hair growth, increase hair growthrate, increase hair number, increase conversion of intermediate hairinto terminal hair, increase hair density, increase number of hairs perfollicle, and/or increase hair pigmentation, increase hair melanization,or any combination thereof.

A composition or compound is administered to an individual. Anindividual is typically a human being. Typically, any individual who isa candidate for a conventional treatment is a candidate for a disorderassociated with androgen production treatment disclosed herein.Pre-operative evaluation typically includes routine history and physicalexamination in addition to thorough informed consent disclosing allrelevant risks and benefits of the procedure.

A pharmaceutical composition disclosed herein may comprise a therapeuticcompound in a therapeutically effective amount. As used herein, the term“effective amount” is synonymous with “therapeutically effectiveamount”, “effective dose”, or “therapeutically effective dose” and whenused in reference to treating a disorder associated with androgenproduction refers to the minimum dose of a therapeutic compounddisclosed herein necessary to achieve the desired therapeutic effect andincludes a dose sufficient to reduce a symptom associated with adisorder associated with androgen production. The effectiveness of atherapeutic compound disclosed herein in treating a disorder associatedwith androgen production can be determined by observing an improvementin an individual based upon one or more clinical symptoms, and/orphysiological indicators associated with the disorder associated withandrogen production. An improvement in a disorder associated withandrogen production also can be indicated by a reduced need for aconcurrent therapy.

The appropriate effective amount of a therapeutic compound disclosedherein to be administered to an individual for a particular disorderassociated with androgen production can be determined by a person ofordinary skill in the art by taking into account factors, including,without limitation, the type of the disorder associated with androgenproduction, the location of the disorder associated with androgenproduction, the cause of the disorder associated with androgenproduction, the severity of the disorder associated with androgenproduction, the degree of relief desired, the duration of reliefdesired, the particular therapeutic compound used, the rate of excretionof the therapeutic compound used, the pharmacodynamics of thetherapeutic compound used, the nature of the other compounds to beincluded in the composition, the particular formulation desired, theparticular route of administration, the particular characteristics,history and risk factors of the patient, such as, e.g., age, weight,general health and the like, or any combination thereof. Additionally,where repeated administration of a therapeutic compound is used, aneffective amount of a therapeutic compound will further depend uponfactors, including, without limitation, the frequency of administration,the half-life of the therapeutic compound, or any combination thereof.In is known by a person of ordinary skill in the art that an effectiveamount of a therapeutic compound disclosed herein can be extrapolatedfrom in vitro assays and in vivo administration studies using animalmodels prior to administration to humans.

Wide variations in the necessary effective amount are to be expected inview of the differing efficiencies of the various routes ofadministration. For instance, oral administration of a therapeuticcompound disclosed herein generally would be expected to require higherdosage levels than administration by inhalation. Similarly, systemicadministration of a therapeutic compound disclosed herein would beexpected to require higher dosage levels than a local administration.Variations in these dosage levels can be adjusted using standardempirical routines of optimization, which are well-known to a person ofordinary skill in the art. The precise therapeutically effective dosagelevels and patterns are preferably determined by the attending physicianin consideration of the above-identified factors. One skilled in the artwill recognize that the condition of the individual can be monitoredthroughout the course of therapy and that the effective amount of atherapeutic compound disclosed herein that is administered can beadjusted accordingly.

In aspects of this embodiment, a therapeutically effective amount of atherapeutic compound disclosed herein reduces a symptom associated witha disorder associated with androgen production by, e.g., at least 10%,at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95% or at least 100%. In other aspects of thisembodiment, a therapeutically effective amount of a therapeutic compounddisclosed herein reduces a symptom associated with a disorder associatedwith androgen production by, e.g., at most 10%, at most 15%, at most20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, atmost 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most75%, at most 80%, at most 85%, at most 90%, at most 95% or at most 100%.In yet other aspects of this embodiment, a therapeutically effectiveamount of a therapeutic compound disclosed herein reduces a symptomassociated with a disorder associated with androgen production by, e.g.,about 10% to about 100%, about 10% to about 90%, about 10% to about 80%,about 10% to about 70%, about 10% to about 60%, about 10% to about 50%,about 10% to about 40%, about 20% to about 100%, about 20% to about 90%,about 20% to about 80%, about 20% to about 20%, about 20% to about 60%,about 20% to about 50%, about 20% to about 40%, about 30% to about 100%,about 30% to about 90%, about 30% to about 80%, about 30% to about 70%,about 30% to about 60%, or about 30% to about 50%.

In aspects of this embodiment, a therapeutically effective amount of atherapeutic compound disclosed herein generally is in the range of about0.01 mg/kg/day to about 50 mg/kg/day. In other aspects of thisembodiment, an effective amount of a therapeutic compound disclosedherein may be, e.g., at least 0.01 mg/kg/day, at least 0.025 mg/kg/day,at least 0.05 mg/kg/day, at least 0.075 mg/kg/day, at least 0.1mg/kg/day, at least 0.25 mg/kg/day, at least 0.5 mg/kg/day, at least0.75 mg/kg/day, at least 1.0 mg/kg/day, at least 2.5 mg/kg/day, at least5.0 mg/kg/day, at least 7.5 mg/kg/day, at least 10 mg/kg/day, at least25 mg/kg/day, or at least 50 mg/kg/day. In yet other aspects of thisembodiment, an effective amount of a therapeutic compound disclosedherein may be, e.g., at least 0.1 mg/kg/day, at least 0.2 mg/kg/day, atleast 0.3 mg/kg/day, at least 0.4 mg/kg/day, at least 0.5 mg/kg/day, atleast 0.6 mg/kg/day, at least 0.7 mg/kg/day, at least 0.8 mg/kg/day, atleast 0.9 mg/kg/day, at least 1.0 mg/kg/day, at least 1.25 mg/kg/day, atleast 1.5 mg/kg/day, at least 1.75 mg/kg/day, at least 2.0 mg/kg/day, atleast 2.25 mg/kg/day, at least 2.5 mg/kg/day, at least 2.75 mg/kg/day,at least 3.0 mg/kg/day, at least 3.25 mg/kg/day, at least 3.5 mg/kg/day,at least 3.75 mg/kg/day, at least 4.0 mg/kg/day, at least 4.25mg/kg/day, at least 4.5 mg/kg/day, at least 4.75 mg/kg/day, or at least5.0 mg/kg/day. In yet other aspects of this embodiment, an effectiveamount of a therapeutic compound disclosed herein may be, e.g., about0.01 mg/kg/day to about 0.1 mg/kg/day, about 0.01 mg/kg/day to about 0.5mg/kg/day, about 0.01 mg/kg/day to about 1 mg/kg/day, about 0.01mg/kg/day to about 5 mg/kg/day, about 0.01 mg/kg/day to about 10mg/kg/day, about 0.1 mg/kg/day to about 0.1 mg/kg/day, about 0.1mg/kg/day to about 0.5 mg/kg/day, about 0.1 mg/kg/day to about 1mg/kg/day, about 0.1 mg/kg/day to about 5 mg/kg/day, or about 0.1mg/kg/day to about 10 mg/kg/day.

In aspects of this embodiment, a therapeutically effective amount of atherapeutic compound disclosed herein generally is in the range of about1 mg/day to about 500 mg/day. In other aspects of this embodiment, aneffective amount of a therapeutic compound disclosed herein may be,e.g., at least 1 mg/day, at least 5 mg/day, at least 10 mg/day, at least25 mg/day, at least 50 mg/day, at least 75 mg/day, at least 100 mg/day,at least 150 mg/day, at least 200 mg/day, at least 250 mg/day, at least300 mg/day, at least 350 mg/day, at least 400 mg/day, at least 450mg/day, or at least 500 mg/day. In yet other aspects of this embodiment,an effective amount of a therapeutic compound disclosed herein may be,e.g., about 1 mg/day to about 100 mg/day, about 1 mg/day to about 150mg/day, about 1 mg/day to about 200 mg/day, about 1 mg/day to about 250mg/day, about 1 mg/day to about 300 mg/day, about 1 mg/day to about 350mg/day, about 1 mg/day to about 400 mg/day, about 1 mg/day to about 450mg/day, about 1 mg/day to about 500 mg/day, about 10 mg/day to about 100mg/day, about 10 mg/day to about 150 mg/day, about 10 mg/day to about200 mg/day, about 10 mg/day to about 250 mg/day, about 10 mg/day toabout 300 mg/day, about 10 mg/day to about 350 mg/day, about 10 mg/dayto about 400 mg/day, about 10 mg/day to about 450 mg/day, or about 10mg/day to about 500 mg/day.

In aspects of this embodiment, a therapeutically effective amount of atherapeutic compound disclosed herein generally is in the range of about1 μM/day to about 1,000 μM/day. In other aspects of this embodiment, aneffective amount of a therapeutic compound disclosed herein may be,e.g., at least 1 μM/day, at least 5 μM/day, at least 10 μM/day, at least50 μM/day, at least 100 μM/day, at least 200 μM/day, at least 300μM/day, at least 400 μM/day, at least 500 μM/day, at least 600 μM/day,at least 700 μM/day, at least 800 μM/day, at least 900 μM/day, or atleast 1,000 μM/day. In yet other aspects of this embodiment, aneffective amount of a therapeutic compound disclosed herein may be,e.g., about 1 μM/day to about 100 μM/day, about 1 μM/day to about 200μM/day, about 1 μM/day to about 400 μM/day, about 1 μM/day to about 600μM/day, about 1 μM/day to about 800 μM/day, about 1 μM/day to about1,000 μM/day, about 10 μM/day to about 100 μM/day, about 10 μM/day toabout 200 μM/day, about 10 μM/day to about 400 μM/day, about 10 μM/dayto about 600 μM/day, about 10 μM/day to about 800 μM/day, about 10μM/day to about 1,000 μM/day, about 25 μM/day to about 100 μM/day, about25 μM/day to about 200 μM/day, about 25 μM/day to about 400 μM/day,about 25 μM/day to about 600 μM/day, about 25 μM/day to about 800μM/day, or about 25 μM/day to about 1,000 μM/day.

In aspects of this embodiment, a therapeutically effective amount of abenzo(iso)oxazolepiperidine disclosed herein generally is in the rangeof about 0.01 mg/kg/day to about 10 mg/kg/day. In other aspects of thisembodiment, an effective amount of a benzo(iso)oxazolepiperidinedisclosed herein may be, e.g., at least 0.01 mg/kg/day, at least 0.025mg/kg/day, at least 0.05 mg/kg/day, at least 0.075 mg/kg/day, at least0.1 mg/kg/day, at least 0.25 mg/kg/day, at least 0.5 mg/kg/day, at least0.75 mg/kg/day, at least 1.0 mg/kg/day, at least 2.5 mg/kg/day, at least5.0 mg/kg/day, at least 7.5 mg/kg/day, or at least 10 mg/kg/day. In yetother aspects of this embodiment, an effective amount of abenzo(iso)oxazolepiperidine disclosed herein may be, e.g., about 0.01mg/kg/day to about 0.1 mg/kg/day, about 0.01 mg/kg/day to about 0.5mg/kg/day, about 0.01 mg/kg/day to about 1 mg/kg/day, about 0.01mg/kg/day to about 5 mg/kg/day, about 0.01 mg/kg/day to about 10mg/kg/day, about 0.1 mg/kg/day to about 0.1 mg/kg/day, about 0.1mg/kg/day to about 0.5 mg/kg/day, about 0.1 mg/kg/day to about 1mg/kg/day, about 0.1 mg/kg/day to about 5 mg/kg/day, or about 0.1mg/kg/day to about 10 mg/kg/day.

In aspects of this embodiment, a therapeutically effective amount of abenzo(iso)oxazolepiperidine disclosed herein generally is in the rangeof about 0.1 mg/day to about 100 mg/day. In other aspects of thisembodiment, an effective amount of a benzo(iso)oxazolepiperidinedisclosed herein may be, e.g., at least 0.1 mg/day, at least 0.5 mg/day,at least 1 mg/day, at least 5 mg/day, at least 10 mg/day, at least 20mg/day, at least 30 mg/day, at least 40 mg/day, at least 50 mg/day, atleast 60 mg/day, at least 70 mg/day, at least 80 mg/day, at least 90mg/day, or at least 100 mg/day. In yet other aspects of this embodiment,an effective amount of a benzo(iso)oxazolepiperidine disclosed hereinmay be, e.g., about 0.1 mg/day to about 10 mg/day, about 0.1 mg/day toabout 20 mg/day, about 0.1 mg/day to about 40 mg/day, about 0.1 mg/dayto about 60 mg/day, about 0.1 mg/day to about 80 mg/day, about 0.1mg/day to about 100 mg/day, about 1 mg/day to about 10 mg/day, about 1mg/day to about 20 mg/day, about 1 mg/day to about 40 mg/day, about 1mg/day to about 60 mg/day, about 1 mg/day to about 80 mg/day, about 1mg/day to about 100 mg/day, about 2.5 mg/day to about 10 mg/day, about2.5 mg/day to about 20 mg/day, about 2.5 mg/day to about 40 mg/day,about 2.5 mg/day to about 60 mg/day, about 2.5 mg/day to about 80mg/day, or about 2.5 mg/day to about 100 mg/day.

In aspects of this embodiment, a therapeutically effective amount of abenzo(iso)oxazolepiperidine disclosed herein generally is in the rangeof about 1 μM/day to about 1,000 μM/day. In other aspects of thisembodiment, an effective amount of a benzo(iso)oxazolepiperidinedisclosed herein may be, e.g., at least 1 μM/day, at least 5 μM/day, atleast 10 μM/day, at least 50 μM/day, at least 100 μM/day, at least 200μM/day, at least 300 μM/day, at least 400 μM/day, at least 500 μM/day,at least 600 μM/day, at least 700 μM/day, at least 800 μM/day, at least900 μM/day, or at least 1,000 μM/day. In yet other aspects of thisembodiment, an effective amount of a benzo(iso)oxazolepiperidinedisclosed herein may be, e.g., about 1 μM/day to about 100 μM/day, about1 μM/day to about 200 μM/day, about 1 μM/day to about 400 μM/day, about1 μM/day to about 600 μM/day, about 1 μM/day to about 800 μM/day, about1 μM/day to about 1,000 μM/day, about 10 μM/day to about 100 μM/day,about 10 μM/day to about 200 μM/day, about 10 μM/day to about 400μM/day, about 10 μM/day to about 600 μM/day, about 10 μM/day to about800 μM/day, about 10 μM/day to about 1,000 μM/day, about 25 μM/day toabout 100 μM/day, about 25 μM/day to about 200 μM/day, about 25 μM/dayto about 400 μM/day, about 25 μM/day to about 600 μM/day, about 25μM/day to about 800 μM/day, or about 25 μM/day to about 1,000 μM/day.

In aspects of this embodiment, in conjunction with abenzo(iso)oxazolepiperidine disclosed herein, a therapeuticallyeffective amount of a fatty acid disclosed herein generally is in therange of about 0.01 mg/kg/day to about 10 mg/kg/day. In other aspects ofthis embodiment, in conjunction with a benzo(iso)oxazolepiperidinedisclosed herein, an effective amount of a fatty acid disclosed hereinmay be, e.g., at least 0.01 mg/kg/day, at least 0.025 mg/kg/day, atleast 0.05 mg/kg/day, at least 0.075 mg/kg/day, at least 0.1 mg/kg/day,at least 0.25 mg/kg/day, at least 0.5 mg/kg/day, at least 0.75mg/kg/day, at least 1.0 mg/kg/day, at least 2.5 mg/kg/day, at least 5.0mg/kg/day, at least 7.5 mg/kg/day, or at least 10 mg/kg/day. In yetother aspects of this embodiment, in conjunction with abenzo(iso)oxazolepiperidine disclosed herein, an effective amount of afatty acid disclosed herein may be, e.g., about 0.01 mg/kg/day to about0.1 mg/kg/day, about 0.01 mg/kg/day to about 0.5 mg/kg/day, about 0.01mg/kg/day to about 1 mg/kg/day, about 0.01 mg/kg/day to about 5mg/kg/day, about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.1mg/kg/day to about 0.1 mg/kg/day, about 0.1 mg/kg/day to about 0.5mg/kg/day, about 0.1 mg/kg/day to about 1 mg/kg/day, about 0.1 mg/kg/dayto about 5 mg/kg/day, or about 0.1 mg/kg/day to about 10 mg/kg/day.

In aspects of this embodiment, in conjunction with abenzo(iso)oxazolepiperidine disclosed herein, a therapeuticallyeffective amount of a fatty acid disclosed herein generally is in therange of about 0.1 mg/day to about 100 mg/day. In other aspects of thisembodiment, an effective amount of a fatty acid disclosed herein may be,e.g., at least 0.1 mg/day, at least 0.5 mg/day, at least 1 mg/day, atleast 5 mg/day, at least 10 mg/day, at least 20 mg/day, at least 30mg/day, at least 40 mg/day, at least 50 mg/day, at least 60 mg/day, atleast 70 mg/day, at least 80 mg/day, at least 90 mg/day, or at least 100mg/day. In yet other aspects of this embodiment, in conjunction with abenzo(iso)oxazolepiperidine disclosed herein, an effective amount of afatty acid disclosed herein may be, e.g., about 0.1 mg/day to about 10mg/day, about 0.1 mg/day to about 20 mg/day, about 0.1 mg/day to about40 mg/day, about 0.1 mg/day to about 60 mg/day, about 0.1 mg/day toabout 80 mg/day, about 0.1 mg/day to about 100 mg/day, about 1 mg/day toabout 10 mg/day, about 1 mg/day to about 20 mg/day, about 1 mg/day toabout 40 mg/day, about 1 mg/day to about 60 mg/day, about 1 mg/day toabout 80 mg/day, about 1 mg/day to about 100 mg/day, about 2.5 mg/day toabout 10 mg/day, about 2.5 mg/day to about 20 mg/day, about 2.5 mg/dayto about 40 mg/day, about 2.5 mg/day to about 60 mg/day, about 2.5mg/day to about 80 mg/day, or about 2.5 mg/day to about 100 mg/day.

In aspects of this embodiment, in conjunction with abenzo(iso)oxazolepiperidine disclosed herein, a therapeuticallyeffective amount of a fatty acid disclosed herein generally is in therange of about 1 μM/day to about 1,000 μM/day. In other aspects of thisembodiment, an effective amount of a fatty acid disclosed herein may be,e.g., at least 1 μM/day, at least 5 μM/day, at least 10 μM/day, at least50 μM/day, at least 100 μM/day, at least 200 μM/day, at least 300μM/day, at least 400 μM/day, at least 500 μM/day, at least 600 μM/day,at least 700 μM/day, at least 800 μM/day, at least 900 μM/day, or atleast 1,000 μM/day. In yet other aspects of this embodiment, inconjunction with a benzo(iso)oxazolepiperidine disclosed herein, aneffective amount of a fatty acid disclosed herein may be, e.g., about 1μM/day to about 100 μM/day, about 1 μM/day to about 200 μM/day, about 1μM/day to about 400 μM/day, about 1 μM/day to about 600 μM/day, about 1μM/day to about 800 μM/day, about 1 μM/day to about 1,000 μM/day, about10 μM/day to about 100 μM/day, about 10 μM/day to about 200 μM/day,about 10 μM/day to about 400 μM/day, about 10 μM/day to about 600μM/day, about 10 μM/day to about 800 μM/day, about 10 μM/day to about1,000 μM/day, about 25 μM/day to about 100 μM/day, about 25 μM/day toabout 200 μM/day, about 25 μM/day to about 400 μM/day, about 25 μM/dayto about 600 μM/day, about 25 μM/day to about 800 μM/day, or about 25μM/day to about 1,000 μM/day.

In aspects of this embodiment, in conjunction with abenzo(iso)oxazolepiperidine disclosed herein, a therapeuticallyeffective amount of a 5α reductase inhibitor disclosed herein generallyis in the range of about 0.01 mg/kg/day to about 10 mg/kg/day. In otheraspects of this embodiment, in conjunction with abenzo(iso)oxazolepiperidine disclosed herein, an effective amount of a5α reductase inhibitor disclosed herein may be, e.g., at least 0.01mg/kg/day, at least 0.025 mg/kg/day, at least 0.05 mg/kg/day, at least0.075 mg/kg/day, at least 0.1 mg/kg/day, at least 0.25 mg/kg/day, atleast 0.5 mg/kg/day, at least 0.75 mg/kg/day, at least 1.0 mg/kg/day, atleast 2.5 mg/kg/day, at least 5.0 mg/kg/day, at least 7.5 mg/kg/day, orat least 10 mg/kg/day. In yet other aspects of this embodiment, inconjunction with a benzo(iso)oxazolepiperidine disclosed herein, aneffective amount of a 5α reductase inhibitor disclosed herein may be,e.g., about 0.01 mg/kg/day to about 0.1 mg/kg/day, about 0.01 mg/kg/dayto about 0.5 mg/kg/day, about 0.01 mg/kg/day to about 1 mg/kg/day, about0.01 mg/kg/day to about 5 mg/kg/day, about 0.01 mg/kg/day to about 10mg/kg/day, about 0.1 mg/kg/day to about 0.1 mg/kg/day, about 0.1mg/kg/day to about 0.5 mg/kg/day, about 0.1 mg/kg/day to about 1mg/kg/day, about 0.1 mg/kg/day to about 5 mg/kg/day, or about 0.1mg/kg/day to about 10 mg/kg/day.

In aspects of this embodiment, in conjunction with abenzo(iso)oxazolepiperidine disclosed herein, a therapeuticallyeffective amount of a 5α reductase inhibitor disclosed herein generallyis in the range of about 0.1 mg/day to about 100 mg/day. In otheraspects of this embodiment, in conjunction with abenzo(iso)oxazolepiperidine disclosed herein, an effective amount of a5α reductase inhibitor disclosed herein may be, e.g., at least 0.1mg/day, at least 0.5 mg/day, at least 1 mg/day, at least 5 mg/day, atleast 10 mg/day, at least 20 mg/day, at least 30 mg/day, at least 40mg/day, at least 50 mg/day, at least 60 mg/day, at least 70 mg/day, atleast 80 mg/day, at least 90 mg/day, or at least 100 mg/day. In yetother aspects of this embodiment, in conjunction with abenzo(iso)oxazolepiperidine disclosed herein, an effective amount of a5α reductase inhibitor disclosed herein may be, e.g., about 0.1 mg/dayto about 10 mg/day, about 0.1 mg/day to about 20 mg/day, about 0.1mg/day to about 40 mg/day, about 0.1 mg/day to about 60 mg/day, about0.1 mg/day to about 80 mg/day, about 0.1 mg/day to about 100 mg/day,about 1 mg/day to about 10 mg/day, about 1 mg/day to about 20 mg/day,about 1 mg/day to about 40 mg/day, about 1 mg/day to about 60 mg/day,about 1 mg/day to about 80 mg/day, about 1 mg/day to about 100 mg/day,about 2.5 mg/day to about 10 mg/day, about 2.5 mg/day to about 20mg/day, about 2.5 mg/day to about 40 mg/day, about 2.5 mg/day to about60 mg/day, about 2.5 mg/day to about 80 mg/day, or about 2.5 mg/day toabout 100 mg/day.

In aspects of this embodiment, in conjunction with abenzo(iso)oxazolepiperidine disclosed herein, a therapeuticallyeffective amount of a 5α reductase inhibitor disclosed herein generallyis in the range of about 1 μM/day to about 1,000 μM/day. In otheraspects of this embodiment, in conjunction with abenzo(iso)oxazolepiperidine disclosed herein, an effective amount of a5α reductase inhibitor disclosed herein may be, e.g., at least 1 μM/day,at least 5 μM/day, at least 10 μM/day, at least 50 μM/day, at least 100μM/day, at least 200 μM/day, at least 300 μM/day, at least 400 μM/day,at least 500 μM/day, at least 600 μM/day, at least 700 μM/day, at least800 μM/day, at least 900 μM/day, or at least 1,000 μM/day. In yet otheraspects of this embodiment, in conjunction with abenzo(iso)oxazolepiperidine disclosed herein, an effective amount of a5α reductase inhibitor disclosed herein may be, e.g., about 1 μM/day toabout 100 μM/day, about 1 μM/day to about 200 μM/day, about 1 μM/day toabout 400 μM/day, about 1 μM/day to about 600 μM/day, about 1 μM/day toabout 800 μM/day, about 1 μM/day to about 1,000 μM/day, about 10 μM/dayto about 100 μM/day, about 10 μM/day to about 200 μM/day, about 10μM/day to about 400 μM/day, about 10 μM/day to about 600 μM/day, about10 μM/day to about 800 μM/day, about 10 μM/day to about 1,000 μM/day,about 25 μM/day to about 100 μM/day, about 25 μM/day to about 200μM/day, about 25 μM/day to about 400 μM/day, about 25 μM/day to about600 μM/day, about 25 μM/day to about 800 μM/day, or about 25 μM/day toabout 1,000 μM/day.

Dosing can be single dosage or cumulative (serial dosing), and can bereadily determined by one skilled in the art. For instance, treatment ofa disorder associated with androgen production may comprise a one-timeadministration of an effective dose of a pharmaceutical compositiondisclosed herein. Alternatively, treatment of a disorder associated withandrogen production may comprise multiple administrations of aneffective dose of a pharmaceutical composition carried out over a rangeof time periods, such as, e.g., once daily, twice daily, trice daily,once every few days, or once weekly. The timing of administration canvary from individual to individual, depending upon such factors as theseverity of an individual's symptoms. For example, an effective dose ofa pharmaceutical composition disclosed herein can be administered to anindividual once daily for an indefinite period of time, or until theindividual no longer requires therapy. A person of ordinary skill in theart will recognize that the condition of the individual can be monitoredthroughout the course of treatment and that the effective amount of apharmaceutical composition disclosed herein that is administered can beadjusted accordingly.

Various routes of administration can be useful for administering atherapeutic compound disclosed herein, according to a method of treatinga disorder associated with androgen production disclosed herein. Apharmaceutical composition may be administered to an individual by anyof a variety of means depending, e.g., on the type of the disorderassociated with androgen production to be treated, the location of thedisorder associated with androgen production to be treated, the specifictherapeutic compound or composition used, or other compound to beincluded in the composition, and the history, risk factors and symptomsof the individual. As such, topical, enteral or parenteral routes ofadministration may be suitable for of treating a disorder associatedwith androgen production disclosed herein and such routes include bothlocal and systemic delivery of a therapeutic compound or compositiondisclosed herein. Compositions comprising either a single therapeuticcompound disclosed herein, or two or more therapeutic compoundsdisclosed herein are intended for inhaled, topical, intranasal,sublingual, injection, infusion, instillation, rectal and/or vaginal usemay be prepared according to any method known to the art for themanufacture of pharmaceutical compositions.

A pharmaceutical composition disclosed herein can be administered to anindividual in a single formulation or in separate formulations, forcombined, simultaneous or sequential administration. In one embodiment,an individual is administered a first composition comprising abenzo(iso)oxazolepiperidine and a second composition comprising anothertherapeutic compound like a fatty acid, a 5α-reductase inhibitor, achemotherapeutic agent, or an anti-proliferative agent. In aspects ofthis embodiment, an individual is administered a first compositioncomprising at least one benzo(iso)oxazolepiperidine and a secondcomposition comprising at least one other therapeutic compound like afatty acid, a 5α-reductase inhibitor, a chemotherapeutic agent, or ananti-proliferative agent.

In another embodiment, an individual is administered a compositioncomprising a benzo(iso)oxazolepiperidine and another therapeuticcompound like a fatty acid, a 5α-reductase inhibitor, a chemotherapeuticagent, or an anti-proliferative agent. In aspects of this embodiment, anindividual is administered a composition comprising at least onebenzo(iso)oxazolepiperidine and at least one other therapeutic compoundlike a fatty acid, a 5α-reductase inhibitor, a chemotherapeutic agent,or an anti-proliferative agent.

A pharmaceutical composition disclosed herein can also be administeredto an individual in combination with other therapeutic compounds toincrease the overall therapeutic effect of the treatment. The use ofmultiple compounds to treat an indication can increase the beneficialeffects while reducing the presence of side effects.

Aspects of the present specification may also be described as follows:

-   1. A composition comprising a therapeutic compound capable of    modulating androgen production.-   2. The composition according to embodiment 1, wherein the    therapeutic compound reduces a symptom of a disorder associated with    androgen production.-   3. The composition according to embodiments 1 or 2, wherein the    therapeutic compound reduces a symptom of a disorder associated with    androgen production by at least 10%.-   4. The composition according to any one of embodiments 1-3, wherein    the therapeutic compound reduces the frequency of a symptom of a    disorder associated with androgen production incurred over a given    time period.-   5. The composition according to any one of embodiments 1-4, wherein    the therapeutic compound reduces the frequency of a symptom of a    disorder associated with androgen production incurred over a given    time period by at least 10%.-   6. The composition according to any one of embodiments 1-5, wherein    the therapeutic compound reduces the number of symptoms of a    disorder associated with androgen production incurred over a given    time period.-   7. The composition according to any one of embodiments 1-6, wherein    the therapeutic compound reduces the number of symptoms of a    disorder associated with androgen production incurred over a given    time period by at least 10%.-   8. The composition according to any one of embodiments 1-7, wherein    the therapeutic compound reduces the severity of a symptom of a    disorder associated with androgen production.-   9. The composition according to any one of embodiments 1-8, wherein    the therapeutic compound reduces the severity of a symptom of a    disorder associated with androgen production by at least 10%.-   10. The composition according to any one of embodiments 1-9, wherein    the disorder associated with androgen production is a disorder    associated with a steroid hydroxy-dehydrogenase activity.-   11. The composition according to any one of embodiments 1-9, wherein    the disorder associated with androgen production is a disorder    associated with a 11β-hydroxysteroid dehydrogenase activity, a    3β-hydroxysteroid dehydrogenase activity, a 17β-hydroxysteroid    dehydrogenase activity, a 20β-hydroxysteroid dehydrogenase activity,    or any combination thereof.-   12. The composition according to embodiment 11, wherein the disorder    associated with a 17β-hydroxysteroid dehydrogenase activity is a    17β-hydroxysteroid dehydrogenase subtype 10 activity.-   13. The composition according to any one of embodiments 1-12,    wherein the therapeutic compound reduces a level of a    dihydrotestosterone.-   14. The composition according to any one of embodiments 1-13,    wherein the therapeutic compound reduces a level of a    dihydrotestosterone by at least 10%.-   15. The composition according to any one of embodiments 1-14,    wherein the therapeutic compound reduces a level of a testosterone,    a level of an androstenedione, a level of an androstenediol, a level    of a dehydroepiandrosterone, or any combination thereof.-   16. The composition according to any one of embodiments 1-15,    wherein the therapeutic compound reduces a level of a level of a    testosterone, a level of an androstenedione, a level of an    androstenediol, a level of a dehydroepiandrosterone, or any    combination thereof by at least 10%.-   17. The composition according to any one of embodiments 1-16,    wherein the therapeutic compound reduces a level of an estrogen.-   18. The composition according to any one of embodiments 1-17,    wherein the therapeutic compound reduces a level of an estrogen by    at least 10%.-   19. The composition according to any one of embodiments 1-18,    wherein the therapeutic compound includes a    benzo(iso)oxazolepiperidine, a fatty acid, a 5α reductase inhibitor,    a chemotherapeutic agent, an anti-proliferative agent, or any    combination thereof.-   20. The composition according to embodiment 19, wherein the    benzo(iso)oxazolepiperidine is an optionally substituted    Iloperidone, an optionally substituted ocaperidone, an optionally    substituted paliperidone, an optionally substituted risperidone, or    any combination thereof.-   21. The composition according to embodiment 19, wherein the fatty    acid is an omega-3 fatty acid, an omega-6 fatty acid, an omega-7    fatty acid, an omega-9 fatty acid, or any combination thereof.-   22. The composition according to embodiment 21, wherein the omega-3    fatty acid is Hexadecatrienoic acid (16:3), α-Linolenic acid (18:3),    Stearidonic acid (18:4), Eicosatrienoic acid (20:3),    Eicosatetraenoic acid (20:4), Eicosapentaenoic acid (20:5),    Heneicosapentaenoic acid (21:5), Docosapentaenoic acid (Clupanodonic    acid) (22:5), Docosahexaenoic acid (22:6), Tetracosapentaenoic acid    (24:5), Tetracosahexaenoic acid (Nisinic acid) (24:6), or any    combination thereof.-   23. The composition according to embodiment 21, wherein the omega-6    fatty acid is Linoleic acid (18:2), γ-linolenic acid (18:3),    Calendic acid (18:3), Eicosadienoic acid (20:2), Dihomo-γ-linolenic    acid (20:3), Arachidonic acid (20:4), Docosadienoic acid (22:2),    Adrenic acid (22:4), Docosapentaenoic acid (22:5),    Tetracosatetraenoic acid (24:4), and Tetracosapentaenoic acid    (24:5), or any combination thereof.-   24. The composition according to embodiment 21, wherein the omega-7    fatty acid is 5-Dodecenoic acid, 7-Tetradecenoic acid,    9-Hexadecenoic acid (Palmitoleic acid), 11-Decenoic acid (Vaccenic    acid), 13-Eicosenoic acid (Paullinic acid), 15-Docosenoic acid,    17-Tetracosenoic acid, and 9Z,11E conjugated Linoleic acid (Rumenic    acid), or any combination thereof.-   25. The composition according to embodiment 21, wherein the omega-9    fatty acid Oleic acid, Elaidic acid, Eicosenoic acid, Mead acid,    Erucic acid, Nervonic acid, and Ricinoleic acid, or any combination    thereof.-   26. The composition according to embodiment 19, wherein the 5α    reductase inhibitor is Alfatradiol, Bexlosteride, Dutasteride,    Epristeride, Finasteride, Isotretinoin, Lapisteride, Turosteride, or    any combination thereof.-   27. The composition according to embodiment 19, wherein the    chemotherapeutic agent or anti-proliferative agent is an alkylating    agent, a platinum agent, an antimetabolite, a topoisomerase    inhibitor, an antitumor antibiotic, an aromatase inhibitor, a    thymidylate synthase inhibitor, a DNA antagonist,    farnesyltransferase inhibitor, a pump inhibitor, a histone    acetyltransferase inhibitor, a metalloproteinase inhibitor, a    ribonucleoside reductase inhibitor, a TNFα agonist, a TNFα    antagonist, an endothelin A receptor antagonist, a retinoic acid    receptor agonist, an immuno-modulator, a hormonal and antihormonal    agent, a photodynamic agent, a tyrosine kinase inhibitor, or any    combination thereof.-   28. The composition according to any one of embodiments 1-27,    wherein the pharmaceutical composition reduces an unwanted side.-   29. The composition according to embodiment 28, wherein the unwanted    side includes feminization in males or defeminisation of females.-   30. The composition according to any one of embodiments 1-29,    wherein the modulating activity of the therapeutic compound reduces    a symptom of a disorder associated with androgen production.-   31. The composition according to embodiment 30, wherein the    modulating activity of the therapeutic compound reduces a symptom of    a disorder associated with androgen production by at least 10%, at    least 15%, at least 20%, at least 25%, at least 30%, at least 35%,    at least 40%, at least 45%, at least 50%, at least 55%, at least    60%, at least 65%, at least 70%, at least 75%, at least 80%, at    least 85%, at least 90%, or at least 95%.-   32. The composition according to embodiment 31, wherein the symptom    includes the frequency of a symptom, the number of symptoms, the    severity of a symptom, or any combination thereof.-   33. The composition according to any one of embodiments 1-32,    wherein the disorder associated with androgen production is a    hormone-dependent disorder.-   34. The composition according to embodiment 33, wherein the    hormone-dependent disorder is a hormone-dependent proliferative    disorder.-   35. The composition according to embodiments 33, wherein the    hormone-dependent disorder is a hormone-dependent non-proliferative    disorder.-   36. The composition according to embodiments 33, wherein the    hormone-dependent disorder is a cancer.-   37. The composition according to embodiment 36, wherein the cancer    is a prostate cancer, a lung cancer, a breast cancer, an ovarian    cancer, testicular cancer.-   38. The composition according to embodiment 36, wherein the cancer    is a hormone-refractory cancer.-   39. The composition according to embodiments 33, wherein the    hormone-dependent disorder is benign prostatic hyperplasia (BPH) or    polycystic ovary syndrome.-   40. The composition according to embodiments 33, wherein the    hormone-dependent disorder is acne vulgaris, seborrhea, or female    hirsutism.-   41. The composition according to embodiments 33, wherein the    hormone-dependent disorder is androgenic alopecia.-   42. The composition according to any one of embodiments 1-41,    wherein the composition includes a benzo(iso)oxazolepiperidine and a    fatty acid.-   43. The composition according to embodiment 42, wherein the    benzo(iso)oxazolepiperidine is an optionally substituted    Iloperidone, an optionally substituted ocaperidone, an optionally    substituted paliperidone, an optionally substituted risperidone, or    any combination thereof.-   44. The composition according to embodiment 42 or 43, wherein the    fatty acid is an omega-3 fatty acid, an omega-6 fatty acid, an    omega-7 fatty acid, an omega-9 fatty acid, or any combination    thereof.-   45. The composition according to any one of embodiments 42-44,    wherein the omega-3 fatty acid is Hexadecatrienoic acid (16:3),    α-Linolenic acid (18:3), Stearidonic acid (18:4), Eicosatrienoic    acid (20:3), Eicosatetraenoic acid (20:4), Eicosapentaenoic acid    (20:5), Heneicosapentaenoic acid (21:5), Docosapentaenoic acid    (Clupanodonic acid) (22:5), Docosahexaenoic acid (22:6),    Tetracosapentaenoic acid (24:5), Tetracosahexaenoic acid (Nisinic    acid) (24:6), or any combination thereof.-   46. The composition according to any one of embodiments 42-45,    wherein the omega-6 fatty acid is Linoleic acid (18:2), γ-linolenic    acid (18:3), Calendic acid (18:3), Eicosadienoic acid (20:2),    Dihomo-γ-linolenic acid (20:3), Arachidonic acid (20:4),    Docosadienoic acid (22:2), Adrenic acid (22:4), Docosapentaenoic    acid (22:5), Tetracosatetraenoic acid (24:4), and    Tetracosapentaenoic acid (24:5), or any combination thereof.-   47. The composition according to any one of embodiments 42-46,    wherein the omega-7 fatty acid is 5-Dodecenoic acid, 7-Tetradecenoic    acid, 9-Hexadecenoic acid (Palmitoleic acid), 11-Decenoic acid    (Vaccenic acid), 13-Eicosenoic acid (Paullinic acid), 15-Docosenoic    acid, 17-Tetracosenoic acid, and 9Z,11E conjugated Linoleic acid    (Rumenic acid), or any combination thereof.-   48. The composition according to any one of embodiments 42-47,    wherein the omega-9 fatty acid Oleic acid, Elaidic acid, Eicosenoic    acid, Mead acid, Erucic acid, Nervonic acid, and Ricinoleic acid, or    any combination thereof.-   49. The composition according to any one of embodiments 1-48,    wherein the composition includes a benzo(iso)oxazolepiperidine and a    5α reductase inhibitor.-   50. The composition according to embodiment 49, wherein the    benzo(iso)oxazolepiperidine is an optionally substituted    Iloperidone, an optionally substituted ocaperidone, an optionally    substituted paliperidone, an optionally substituted risperidone, or    any combination thereof.-   51. The composition according to embodiment 49 or 50, wherein the 5α    reductase inhibitor is Alfatradiol, Bexlosteride, Dutasteride,    Epristeride, Finasteride, Isotretinoin, Lapisteride, Turosteride, or    any combination thereof.-   52. The composition according to any one of embodiments 1-48,    wherein the composition includes a benzo(iso)oxazolepiperidine and a    chemotherapeutic agent or an anti-proliferative agent.-   53. The composition according to embodiment 54, wherein the    benzo(iso)oxazolepiperidine is an optionally substituted    Iloperidone, an optionally substituted ocaperidone, an optionally    substituted paliperidone, an optionally substituted risperidone, or    any combination thereof.-   54. The composition according to embodiment 52 or 53, wherein the    chemotherapeutic agent or anti-proliferative agent is an alkylating    agent, a platinum agent, an antimetabolite, a topoisomerase    inhibitor, an antitumor antibiotic, an aromatase inhibitor, a    thymidylate synthase inhibitor, a DNA antagonist,    farnesyltransferase inhibitor, a pump inhibitor, a histone    acetyltransferase inhibitor, a metalloproteinase inhibitor, a    ribonucleoside reductase inhibitor, a TNFα agonist, a TNFα    antagonist, an endothelin A receptor antagonist, a retinoic acid    receptor agonist, an immuno-modulator, a hormonal and antihormonal    agent, a photodynamic agent, a tyrosine kinase inhibitor, or any    combination thereof.-   55. A method of treating an individual with a disorder associated    with androgen production, the method comprises the step of    administering to an individual in need thereof a pharmaceutical    composition as defined in embodiments 1-54, wherein administration    reduces a symptom of a disorder associated with androgen production,    thereby treating the individual.-   56. The method according to embodiment 55, wherein administration of    the pharmaceutical composition reduces the occurrence of an unwanted    side.-   57. The method according to embodiment 56, wherein the unwanted side    includes feminization in males or defeminisation of females.-   58. The method according to any one of embodiments 55-57, wherein    the symptom is reduced by at least 10%, at least 15%, at least 20%,    at least 25%, at least 30%, at least 35%, at least 40%, at least    45%, at least 50%, at least 55%, at least 60%, at least 65%, at    least 70%, at least 75%, at least 80%, at least 85%, at least 90%,    or at least 95%.-   59. The method according to any one of embodiments 55-58, wherein    the symptom includes the frequency of a symptom, the number of    symptoms, the severity of a symptom, or any combination thereof.-   60. The method according to any one of embodiments 55-59, wherein    the therapeutically effective amount of the therapeutic compound is    in the range of about 0.01 mg/kg/day to about 50 mg/kg/day.-   61. The method according to any one of embodiments 55-60, wherein    the therapeutically effective amount of the therapeutic compound is    in the range of about 1 mg/day to about 500 mg/day.-   62. The method according to any one of embodiments 55-60, wherein    the therapeutically effective amount of the therapeutic compound is    in the range of about 1 μM/day to about 1,000 μM/day.-   63. The method according to any one of embodiments 55-62, wherein    the disorder associated with androgen production.-   64. The method according to embodiment 63, wherein the disorder    associated with androgen production is a disorder associated with    steroid hydroxy-dehydrogenase activity, a disorder associated with    HSD17B activity, a disorder associated with HSD17B10 activity, or    any combination thereof.-   65. The method according to embodiment 63, wherein the disorder    associated with androgen production is a hormone-dependent disorder.-   66. The method according to embodiment 65, wherein the    hormone-dependent disorder is a hormone-dependent proliferative    disorder.-   67. The method according to embodiments 65, wherein the    hormone-dependent disorder is a hormone-dependent non-proliferative    disorder.-   68. The method according to embodiments 65, wherein the    hormone-dependent disorder is a cancer.-   69. The method according to embodiment 68, wherein the cancer is a    prostate cancer, a lung cancer, a breast cancer, an ovarian cancer,    testicular cancer.-   70. The method according to embodiment 68, wherein the cancer is a    hormone-refractory cancer.-   71. The method according to embodiments 65, wherein the    hormone-dependent disorder is benign prostatic hyperplasia (BPH) or    polycystic ovary syndrome.-   72. The method according to embodiments 65, wherein the    hormone-dependent disorder is acne vulgaris, seborrhea, or female    hirsutism.-   73. The method according to embodiments 65, wherein the    hormone-dependent disorder is androgenic alopecia.-   74. Use of a pharmaceutical composition as defined in embodiments    1-54 for the manufacture of a medicament for the treatment of a    disorder associated with androgen production.-   75. Use of a pharmaceutical composition as defined in embodiments    1-54 for treating a disorder associated with androgen production.-   76. The use according to embodiment 74 or 75, wherein administration    of the pharmaceutical composition reduces the occurrence of an    unwanted side.-   77. The use according to embodiment 76, wherein the unwanted side    includes feminization in males or defeminisation of females.-   78. The use according to any one of embodiments 74-77, wherein the    symptom is reduced by at least 10%, at least 15%, at least 20%, at    least 25%, at least 30%, at least 35%, at least 40%, at least 45%,    at least 50%, at least 55%, at least 60%, at least 65%, at least    70%, at least 75%, at least 80%, at least 85%, at least 90%, or at    least 95%.-   79. The use according to any one of embodiments 74-78, wherein the    symptom includes the frequency of a symptom, the number of symptoms,    the severity of a symptom, or any combination thereof.-   80. The use according to any one of embodiments 74-79, wherein the    amount of the therapeutic compound administered is in the range of    about 0.01 mg/kg/day to about 50 mg/kg/day.-   81. The use according to any one of embodiments 74-79, wherein the    amount of the therapeutic compound administered is in the range of    about 1 mg/day to about 500 mg/day.-   82. The use according to any one of embodiments 74-79, wherein the    amount of the therapeutic compound administered is in the range of    about 1 μM/day to about 1,000 μM/day.

EXAMPLES

The following non-limiting examples are provided for illustrativepurposes only in order to facilitate a more complete understanding ofrepresentative embodiments now contemplated. These examples should notbe construed to limit any of the embodiments described in the presentspecification, including those pertaining to the compounds,pharmaceutical compositions, or methods or uses of treating a disorderdisclosed herein.

Example 1 HSD10 Enzyme Inhibition Assay

An HSD10 inhibition assay was performed to determine the effect ofseveral anti-psychotics on enzyme activity.

PC3 cells are from a cell line derived from a hormone refractoryprostate cancer and are known to overexpress HSD10. PC3 cells wereseeded at a density of 4,000 cells per well in a 96 well plate, andincubated at 37° C., 5% CO₂ for 48 hours in standard growth media (F12Knutrient media, 7% Fetal Calf Serum, 2 mM L-Glutamine, 45 mg/L ascorbicacid). The media was then removed by pipette and replaced with theappropriate drug treatment as follows: 50 μM Chlorpromazine (a typicalanti-psychotic) in PC3 treatment media (F12K nutrient media, 125 μMfatty acid free BSA, 2 mM L-Glutamine, 45 mg/L ascorbic acid); 50 μMClozapine (an atypical anti-psychotic) in PC3 treatment media; 50 μMClomipramine (a tricyclic anti-depressant) in PC3 treatment media; 50 μMRisperidone (an atypical anti-psychotic) in PC3 treatment media; 50 μMDiphenhydramine (a sedative) in PC3 treatment media. Cells line testswere carried out in presence and absence of testosterone for comparison.After incubation in the drug treatment for 96 hours at 37° C., 5% CO₂,the supernatant was removed from all wells of cells, and cells washedwith 200 μL PBS.

After removal of the PBS, cell number was determined using a lysed cellLDH assay (CytoTox 96 Non-radioactive cytotoxicity assay (LDH Assay);Promega, Co., Madison Wis.). Cells were lysed with 0.9% Triton-X in PBSfor 2 hours at 37° C., 5% CO₂ and 50 μL of this cell lysate wastransferred to a fresh 96 well plate. About 50 μL of CytoTox 96 assayreagent was added to the transferred cell lysate and this mixture wasincubated at room temperature in the dark for 20 minutes. After theaddition of 50 μL stop reagent, the optical absorbance was determinedfor each incubated mixture at 492 nm. The percentage cell number wascalculated by normalizing the experimental counts, where 100% is set tocells receiving no drug treatment, and 0% is set to readings from wellscontaining no cells. The mean and standard error was calculated from atleast 3 wells.

As seen in Table 1, Risperidone showed an inhibitory effect on bothoxidative (88% inhibition) and reductive (63% inhibition) performance ofHSD10. No other drug tested appeared to have effectively inhibited bothoxidative and reductive performance of HSD10.

TABLE 1 HSD10 Enzymatic Activity in Presence of Different DrugsOxidative Activity Reductive Activity Rate Drug Rate Drug Drug (μM/min)Inhibition (μM/min) Inhibition No Drug 8.4  0% 8.8  0% Chlorpromazine7.7  8% 7.2 18% Clozapine 4.8 43% 7.5 15% Clomipramine 2.3 73% 7.5 15%Risperidone 1.0 88% 3.3 63% Diphenhydramine 8.0  5% 8.3  6%

A cell metabolism inhibition assay was performed to determine the effectof different fatty acids on cellular metabolic rate. The fatty acidstested were α-Linolenic acid, omega 3 fatty acid (ALA), Arachidonicacid, omega 6 fatty acid (AA), 9Z, 11E conjugated Linoleic acid, omega 7fatty acid (CLA), Docosahexaenoic acid, omega 3 fatty acid (DHA),Eicosapentaenoic acid, omega 3 fatty acid (EPA), Oleic acid, omega 9fatty acid (OA), Ricinoleic acid, omega 9 hydroxylated fatty acid (RA).

PC3 cells are from a cell line derived from a hormone refractoryprostate cancer and are known to overexpress HSD10. PC3 cells wereseeded at a density of 4,000 cells per well in a 96 well plate, andincubated at 37° C., 5% CO₂ for 48 hours in standard growth media (F12Knutrient media, 7% Fetal Calf Serum, 2 mM L-Glutamine, 45 mg/L ascorbicacid). The media was then removed by pipette and replaced with theappropriate drug treatment as follows: 20 μM, or 40 μM, or 60 μM, or 80μM, or 100 μM ALA in PC3 treatment media (F12K nutrient media, 125 uMfatty acid free BSA, 2 mM L-Glutamine, 45 mg/L ascorbic acid); 20 μM, or40 μM, or 60 μM, or 80 μM, or 100 μM AA in PC3 treatment media; 20 μM,or 40 μM, or 60 μM, or 80 μM, or 100 μM CLA in PC3 treatment media; 20μM, or 40 μM, or 60 μM, or 80 μM, or 100 μM DHA in PC3 treatment media;20 μM, or 40 μM, or 60 μM, or 80 μM, or 100 μM EPA in PC3 treatmentmedia; 20 μM, or 40 μM, or 60 μM, or 80 μM, or 100 μM OA in PC3treatment media; and 20 μM, or 40 μM, or 60 μM, or 80 μM, or 100 μM RAin PC3 treatment media. After incubation in the drug treatment for 72hours at 37° C., 5% CO₂, 50 μL Cell titre Blue Assay Reagent was addedto each well and the plate return to incubation at 37° C., 5% CO₂, for afurther 24 hours, at which time the absorbance at 620 nm was recorded.The reduction of absorbance at 620 nm represents a higher metabolicrate, and the data below has been normalized such that 100% representscells that have been grown in the presence of undrugged media, and 0%represents wells containing no cells.

As seen in Table 2, AA, CLA, DHA, and EPA showed a significantinhibitory effect on cellular metabolic activity. AA showed about 35-40%metabolic inhibition in the 80-100 μM range. CLA showed at least about35-40% metabolic inhibition in the 60-100 μM range. DHA showed about40-65% metabolic inhibition in the 60-100 μM range. EPA showed about50-65% metabolic inhibition in the 80-100 μM range.

TABLE 2 Cellular Metabolic Activity in Presence of Different Fatty AcidsFatty Acid 20 μM 40 μM 60 μM 80 μM 100 μM ALA 118 ± 0.5  118 ± 0.9  118± 0.2  117 ± 0.9  114 ± 1.2  AA 107 ± 3.9  90 ± 5.6 78 ± 6.4 66 ± 7.2 60± 5.9 CLA 86 ± 2.4 71 ± 3.8 59 ± 2.8 63 ± 4.0 67 ± 5.0 DHA 90 ± 8.2 74 ±7.6 58 ± 5.9 49 ± 7.7 34 ± 7.0 EPA 94 ± 9.4 71 ± 8.2 67 ± 7.4 49 ± 7.437 ± 5.9 OA 109 ± 2.7  108 ± 0.9  111 ± 2.2  110 ± 2.2  111 ± 2.0  RA 91± 6.0 94 ± 4.7 90 ± 6.2 90 ± 6.0 94 ± 3.1

Example 2 Cell Growth Inhibition Assay

To determine whether Risperidone could be effective in inhibiting growthof cancer cells overexpressing HSD10, a lysed cell LDH assay wasconducted using cells from a PC3 cell line.

PC3 cells are from a cell line derived from a hormone refractoryprostate cancer and are known to overexpress HSD10. PC3 cells wereseeded at a density of 4,000 cells per well in a 96 well plate, andincubated at 37° C., 5% CO₂ for 48 hours in standard growth media (F12Knutrient media, 7% Fetal Calf Serum, 2 mM L-Glutamine, 45 mg/L ascorbicacid). The media was then removed by pipette and replaced with theappropriate drug treatment as follows: 12.5 μM, 25 μM, or 50 μMRisperidone in PC3 treatment media (F12K nutrient media, 125 uM fattyacid free BSA, 2 mM L-Glutamine, 45 mg/L ascorbic acid); 12.5 μM, 25 μM,or 50 μM CLA in PC3 treatment media; 12.5 μM, 25 μM, or 50 μM DHA in PC3treatment media; 12.5 μM Risperidone and 12.5 μM CLA, DHA, or both CLAand DHA in PC3 treatment media; 25 μM Risperidone and 25 μM CLA, DHA, orboth CLA and DHA in PC3 treatment media; and 50 μM Risperidone and 50 μMCLA, DHA, or both CLA and DHA in PC3 treatment media. Cells line testswere carried out in presence and absence of testosterone for comparison.After incubation in the drug treatment for 96 hours at 37° C., 5% CO₂,the supernatant was removed from all wells of cells, and cells washedwith 200 μL PBS.

After removal of the PBS, cell number was determined using a lysed cellLDH assay (CytoTox 96 Non-radioactive cytotoxicity assay (LDH Assay);Promega, Co., Madison Wis.). Cells were lysed with 0.9% Triton-X in PBSfor 2 hours at 37° C., 5% CO₂ and 50 μL of this cell lysate wastransferred to a fresh 96 well plate. About 50 μL of CytoTox 96 assayreagent was added to the transferred cell lysate and this mixture wasincubated at room temperature in the dark for 20 minutes. After theaddition of 50 μL stop reagent, the optical absorbance was determinedfor each incubated mixture at 492 nm. The percentage cell number wascalculated by normalizing the experimental counts, where 100% is set tocells receiving no drug treatment, and 0% is set to readings from wellscontaining no cells. The mean and standard error was calculated from atleast 3 wells.

The results show that 50 μM Risperidone exhibited about 50% growthinhibition of PC3 cells (Table 3). In addition, although having noeffect alone, CLA in combination Risperidone had a synergistic effect,inhibiting PC3 cell growth by over 60%.

TABLE 3 Anti-Cancer Activity of Risperidone in PC3 Cells Percentage ofLysed Cells (%) Risperidone Risperidone Risperidone plus ConcentrationRisperidone plus CLA plus DHA DHA/CLA CLA DHA 12.5 μM   102 ± 5.4  104 ±3.2  114 ± 5.5  113 ± 1.6   109 ± 0.56 109 ± 1.1 25 μM 93 ± 0.51 85 ±1.7 102 ± 0.12 88 ± 1.9  112 ± 1.1 102 ± 3.5 50 μM 52 ± 0.22 38 ± 1.8 66± 3.4 36 ± 0.47 107 ± 2.4  95 ± 3.8

To determine the optimal concentration of Risperidone and CLA necessaryto inhibit cell growth, a lysed cell LDH assay was conducted usingvarious concentration of Risperidone and CLA. PC3 cells were culturedand a lysed cell LDH assay was conducted as described above, except thatthe various drug treatments evaluated contained either 0 μM, 12.5 μM, 25μM, or 50 μM Risperidone in combination with 0 μM, 6.25 μM, 12.5 μM, 25μM, 50 μM, or 100 μM CLA (see Table 3).

The data demonstrated that combination treatments comprising 50 μMRisperidone and either 50 or 100 μM CLA exhibited about 65% growthinhibition of PC3 cells (Table 4). In addition, 50 μM Risperidone and 25μM CLA or 25 μM Risperidone and 50 μM CLA both exhibited about 50%growth inhibition of PC3 cells (Table 4). These inhibitory effects wereall synergistic in nature since treatment containing either 25 μM or 50μM Risperidone alone only inhibited cell growth by about 20-30%.

TABLE 4 Anti-Cancer Activity of Risperidone and CLA Combinations in PC3Cells Percentage of Lysed Cells (%) Risperidone CLA ConcentrationConcentration 0 μM 6.25 μM 12.5 μM 25 μM 50 μM 100 μM  0 μM 100 96 ± 0.790 ± 2.7 112 ± 9.5  103 ± 9.3  66 ± 11.8 12.5 μM   81 ± 3.6 114 ± .2.2 112 ± 7.1  95 ± 2.5 — — 25 μM 73 ± 2.2 — 94 ± 1.8 89 ± 6.8 54 ± 2.8 — 50μM 79 ± 0.7 — — 55 ± 2.6  36 ± 0.81 34 ± 1.2 

Example 3 Cell Growth Inhibition Assay

To determine whether Risperidone could be effective in inhibiting growthof cancer cells overexpressing HSD10, a lysed cell LDH assay wasconducted using cells taken from a prostate cancer cell line, a lungcancer cell line, a breast cancer cell line, an ovarian cancer cellline, each of which was known to overexpress HSD10, and a non-cancerouscell line.

To determine whether Risperidone alone, or in combination with CLA couldinhibit cell growth of cells taken from a prostate cancer cell lineoverexpressing HSD10, a lysed cell LDH assay was conducted on PC3 cellsas described in Example 2, except that the various drug treatmentsevaluated contained: 50 μM Risperidone in PC3 treatment media; 50 μM CLAin PC3 treatment media; 50 μM Risperidone and 50 μM CLA in PC3 treatmentmedia; 50 μM Risperidone and 1 μM Testosterone (T) in PC3 treatmentmedia; 50 μM Risperidone, 50 μM CLA, and 1 μM Testosterone in PC3treatment media.

To determine whether Risperidone alone, or in combination with CLA couldinhibit cell growth of cells taken from a lung cancer cell lineoverexpressing HSD10, A549 cells were seeded at a density of 2,000 cellsper well in a 96 well plate, and incubated at 37° C., 5% CO₂ for 48hours in standard growth media (DMEM nutrient media, 10% Fetal CalfSerum, 2 mM L-Glutamine). The media was then removed by pipette andreplaced with the appropriate drug treatment as follows: 50 μMRisperidone in A459 treatment media (DMEM nutrient media, 125 uM fattyacid free BSA, 2 mM L-Glutamine); 50 μM CLA in A459 treatment media; 50μM Risperidone and 50 μM CLA in A459 treatment media; 50 μM Risperidoneand 1 μM Testosterone in A459 treatment media; 50 μM Risperidone, 50 μMCLA, and 1 μM Testosterone in A459 treatment media. After incubation inthe drug treatment for 96 hours at 37° C., 5% CO₂, the supernatant wasremoved from all wells of cells, and cells washed with 200 μL PBS.

To determine whether Risperidone alone, or in combination with CLA couldinhibit cell growth of cells taken from a breast cancer cell lineoverexpressing HSD10, MCF7 cells were seeded at a density of 4,000 cellsper well in a 96 well plate, and incubated at 37° C., 5% CO₂ for 48hours in standard growth media (EMEM nutrient media, 10% Fetal CalfSerum, 2 mM L-Glutamine, 0.1 mM non-essential amino acids). The mediawas then removed by pipette and replaced with the appropriate drugtreatment as follows: 50 μM Risperidone in MCF7 treatment media (EMEMnutrient media, 125 uM fatty acid free BSA, 2 mM L-Glutamine, 0.1 mMnon-essential amino acids); 50 μM CLA in MCF7 treatment media; 50 μMRisperidone and 50 μM CLA in MCF7 treatment media; 50 μM Risperidone and1 μM Testosterone in MCF7 treatment media; 50 μM Risperidone, 50 μM CLA,and 1 μM Testosterone in MCF7 treatment media. After incubation in thedrug treatment for 96 hours at 37° C., 5% CO₂, the supernatant wasremoved from all wells of cells, and cells washed with 200 μL PBS.

To determine whether Risperidone alone, or in combination with CLA couldinhibit cell growth of cells taken from an ovarian cancer cell lineoverexpressing HSD10, OVCAR-3 cells were seeded at a density of 8,000cells per well in a 96 well plate, and incubated at 37° C., 5% CO₂ for48 hours in standard growth media (RPMI-1640 nutrient media, 20% FetalCalf Serum, 2 mM L-Glutamine, 0.01 mg/mL insulin, 4.5 g/L glucose, 10 mMHEPES, 1 mM sodium pyruvate). The media was then removed by pipette andreplaced with the appropriate drug treatment as follows: 50 μMRisperidone in OVCAR-3 treatment media (RPMI-1640 nutrient media, 0.5%Fetal Calf Serum, 125 uM fatty acid free BSA, 2 mM L-Glutamine, 0.01mg/mL insulin, 4.5 g/L glucose, 10 mM HEPES, 1 mM sodium pyruvate); 50μM CLA in OVCAR-3 treatment media; 50 μM Risperidone and 50 μM CLA inOVCAR-3 treatment media; 50 μM Risperidone and 1 μM Testosterone inOVCAR-3 treatment media; 50 μM Risperidone, 50 μM CLA, and 1 μMTestosterone in OVCAR-3 treatment media. After incubation in the drugtreatment for 96 hours at 37° C., 5% CO₂, the supernatant was removedfrom all wells of cells, and cells washed with 200 μL PBS.

To determine whether Risperidone alone, or in combination with CLA couldinhibit cell growth of cells taken from a non-cancerous cell line, VEROcells, derived from kidney cells) were seeded at a density of 2,000cells per well in a 96 well plate, and incubated at 37° C., 5% CO₂ for48 hours in standard growth media (EMEM nutrient media, 10% Fetal CalfSerum, 2 mM L-Glutamine, 1 mM sodium pyruvate). The media was thenremoved by pipette and replaced with the appropriate drug treatment asfollows: 50 μM Risperidone in VERO treatment media (EMEM nutrient media,125 uM fatty acid free BSA, 2 mM L-Glutamine, 1 mM sodium pyruvate); 50μM CLA in VERO treatment media; 50 μM Risperidone and 50 μM CLA in VEROtreatment media; 50 μM Risperidone and 1 μM Testosterone in VEROtreatment media; 50 μM Risperidone, 50 μM CLA, and 1 μM Testosterone inVERO treatment media. After incubation in the drug treatment for 96hours at 37° C., 5% CO₂, the supernatant was removed from all wells ofcells, and cells washed with 200 μL PBS.

After removal of the PBS from the cell cultures described above, cellnumber was determined using a lysed cell LDH assay. Cells were lysedwith 0.9% Triton-X in PBS for 2 hours at 37° C., 5% CO₂ and 50 μL ofthis cell lysate was transferred to a fresh 96 well plate. About 50 μLof CytoTox 96 assay reagent was added to the transferred cell lysate andthis mixture was incubated at room temperature in the dark for 20minutes. After the addition of 50 μL stop reagent, the opticalabsorbance was determined for each incubated mixture at 492 nm. Thepercentage cell number was calculated by normalizing the experimentalcounts, where 100% is set to cells receiving no drug treatment, and 0%is set to readings from wells containing no cells. The mean and standarderror was calculated from at least 3 wells.

The results show that 50 μM Risperidone exhibited about 50% growthinhibition of PC3 cells, over 60% growth inhibition of A549 cells, about65% growth inhibition of MCF7 cells, and about 35% growth inhibition ofOVCAR-3 cells (Table 3). In addition, CLA in combination Risperidonedemonstrated a synergistic growth inhibition effect on most cancer celllines tested. Thus, 50 μM Risperidone in combination with CLA exhibitedover 60% growth inhibition of PC3 cells, almost 100% growth inhibitionof A549 cells, and over 70% growth inhibition of MCF7 cells (Table 3).Importantly, neither Risperidone nor CLA had any measurable effect ongrowth on cell from the non-cancerous cell line VERO.

The results also show that the mechanism of action of Resperidone isrelated to Testosterone in that adding an external source ofTestosterone to Risperidone-treated cells partially negated the effectof the Risperidone alone. However, in the presence of CLA, Testosteronefailed to negate the effect of the Risperidone. This suggests the CLA isacting on one Testosterone pathway and Risperidone on anotherTestosterone pathway. None of the cells from the cell lines testedresponded to a 1 μM Testosterone treatment without drug present.

TABLE 5 Anti-Cancer Activity of Risperidone in Various Cancer CellsPercentage of Lysed Cells (%) Risperi- Risperidone RisperidoneRisperidone Cell Line done CLA plus CLA plus T plus CLA/T PC3 52 ± 1.7107 ± 2.4  38 ± 1.8 67 ± 2.8 41 ± 4.3 A549 38 ± 1.9 4.5 ± 0.3   1 ± 0.148 ± 4.1  1 ± 0.1 MCF7 35 ± 2.4 56 ± 2.6 28 ± 0.6 54 ± 3.6 26 ± 1.1OVCAR-3 64 ± 0.4 87 ± 6.0 69 ± 2.1 84 ± 4.0 70 ± 1.8 VERO 94 ± 1.7 98 ±2.7 94 ± 3.5 96 ± 0.9 98 ± 1.8

Example 4 In Vivo Animal Model Studies

In vivo studies were performed to determine the effect of Risperidone incombination with Rumenic acid in prostate cancer orthotopic xenografts.Nude male mice were acclimated to the laboratory for at least one weekprior to implantation of tumor. PC-3M-luc cells obtained directly fromin vitro culture were then injected into the prostate on Day 0. Animalswere divided into six groups of 12 mice each. Primary tumor size andmetastases were assessed by bioluminescence measurements on day 6, 13,20, 27, 34, and 40. On day 7 a five week treatment regime was initiated.Both individual drug and high and low dose combination were examined byadministering the drugs twice daily on an individual body weight basisusing a dose escalation protocol (Table 6). If tumors grew above apre-determined level, or mice lost more than 10% of bodyweight, theywere culled. The primary tumor was excised, weighed and measured.Individual organs were imaged to assess metastatic burden.

TABLE 6 Dosing Regime of Animal Groups Animal Group 4 5 1 2 3 Low DoseHigh Dose 6 Day Vehicle Risperidone Rumenic Acid Combination*Combination* Docetaxel 7 — 0.25 mg/kg 0.18 mg/kg 0.25 mg/kg 1:1 0.25mg/kg 1:1 5 mg/kg i.v. oral BID oral BID combination combination twiceweekly, oral BID oral BID plus BID oral vehicle (as Group 1) 11 — 0.5mg/kg oral 0.35 mg/kg 0.5 mg/kg1:1 0.5 mg/kg1:1 5 mg/kg i.v. BID oralBID combination combination twice weekly, oral BID oral BID plus BIDoral vehicle (as Group 1) 15 — 1.0 mg/kg oral 0.70 mg/kg 0.5 mg/kg1:11.0 mg/kg1:1 5 mg/kg i.v. BID oral BID combination combination twiceweekly, oral BID oral BID plus BID oral vehicle (as Group 1)*combination doses were calculated according to the dosage ofRisperidone; rumenic acid was added to an equimolar level.

One parameter of increased efficacy measured was animal survival in eachgroup, both in terms of overall survival at the end of the study as wellas survival rate. Group 1 animals were dosed on a vehicle and served asthe negative control and exhibited an overall survivorship of 45% (Table7). Group 6 animals were dosed on Docetaxel and served as the positivecontrol; this group showed 100% survival at day 40 (Table 7). Looking atthe groups where only a single drug was administered, Group 2(Risperidone) showed an overall survivorship of 33% while Group 3(Rumenic Acid) showed an overall survivorship of 45% (Table 7). Theseresults indicate that administration of a single drug alone wasineffective in treating prostate cancer. On the other hand, groups wherea drug combination was administered revealed increased overallsurvivorship of animals. Animals from Group 4 and 5 were dosed low andhigh Risperidone and Rumenic Acid combinations. Group 4 animals showedan overall survivorship of 70% while Group 5 animals showed an overallsurvivorship of 64% (Table 6). These results demonstrate a synergisticinteraction between Risperidone and Rumenic Acid as neither drug alonewas effective, yet in combination these drugs increased overall survivalby at least 1.4-fold and as much as 2.1-fold. Thus, both the low andhigh dose drug combinations exhibited increase efficacy by improvingoverall survivorship in the treated animals.

TABLE 7 Dosing Regime of Animal Groups Animal Tumor Growth GroupSurvival Inhibition* 1 45%  0% 2 33% 16% 3 45% 21% 4 70% 70% 5 64% 65% 6100%  94% *Tumor growth inhibition data is as calculated on Day 34,except for Group 5 which had sufficient mice alive to calculate on Day40.

With regards to survival rate, a decline in the survival of Group 1(Vehicle) animals was observed by day 27 with an almost 20% animal lossand continued to drop steadily throughout the course of the study (FIG.2). Group 6 (Docetaxel) animals showed 100% survival throughout thecourse of the study (FIG. 2). Similar to overall survivorship, animalsbelonging to the groups where only a single drug was administered showedno real differences when compared to Group 1 animals (negative control).For example, animals from Group 2 (Risperidone) showed an onset delay oftumor lethality as a decrease in survivorship rate was pushed back today 34 with only about 10% animal loss. However, a rapid decrease ofsurvive rate was then observed resulting in only 33% animal survivorshipby day 40 (FIG. 2). Similarly, animals from Group 3 (Rumenic Acid)showed a decline in the survival rate by day 27. Although survivalremained high with only about 10% animal loss by day 34, there was asharp decline in survival rates until only 45% of the mice were alive byday 40 (FIG. 2). In contrast, both the onset of tumor lethality and thesurvival rate improved in animals treated with the combination therapy.For example, a decline in survival rate was not observed until day 34with about 10% (Group 5) or 34% (Group 4) loss of animals (FIG. 2). Byday 40, 70% of the animals in Group 4 were alive whereas 64% of theanimals in Group 5 were also alive (FIG. 2). These results demonstratethat both the low and high dose drug combinations showed increaseefficacy by increasing survival rates both in terms of delaying theonset of tumor lethality and well as improving the survival rate in thetreated animals.

Another parameter of increased efficacy measured was growth inhibitionof the prostate tumor. Group 1 (Vehicle) animals severing as thenegative control showed no inhibition of tumor growth, whereas Group 6(Docetaxel) animals severing as the positive control showed a 94%inhibition of tumor growth (Table 7). Animal groups treated with asingle drug regime showed little effect on tumor growth inhibition.Animals from Group 2 (Risperidone) showed only a 16% inhibition of tumorgrowth (Table 7). Similarly, Group 3 (Rumenic Acid) animals showed onlya 21% inhibition of tumor growth (Table 7). In contrast, animal groupstreated with both low and high dose drug combinations exhibitedsignificant tumor growth inhibition. For example, animals from Group 4(Low Dose) showed 70% inhibition of tumor growth whereas animals fromGroup 5 (High Dose) showed 65% inhibition of tumor growth (Table 7).Analysis of tumor growth inhibition throughout the course of the studyindicated that the rate of tumor growth inhibition was consistent (FIG.3). These results demonstrate that both the low and high dose drugcombinations showed increase efficacy by dramatically inhibiting tumorgrowth.

Lastly, the general health and overall condition of the animals in eachgroup was assessed by monitoring body weight throughout the study.Groups 1 (Vehicle) and Group 6 (Docetaxel) animals were on a trend oflosing weight by Day 40, whereas Group 4 animals gained weight andGroups 2, 3, 5 animals maintained a constant weight. These resultsshowed that both the low and high dose drug combinations did notadversely affect the general health and overall condition of theanimals. In contrast, although demonstrating efficacy, Docetaxeladministration had adverse consequences on the general health andoverall condition of the animals.

Example 5 Treatment of a Disorder Associated with Androgen Production

A 58 year old man complains of difficulty in urinating. After routinehistory and physical examination, a physician diagnosis the man withprostate cancer. The man is treated systemically by intravenousadministration a pharmaceutical composition comprising Risperidone andRumenic acid as disclosed herein. The patient's condition is monitoredand after about one month after treatment, the physician determines thatthe size of the prostate has become smaller. At three and six monthcheck-ups, the physician determines that there is a further decrease inthe size of the tumor and that serum PSA levels are within the normalrange. This reduction in tumor size and/or reduces serum PSA levelsindicates successful treatment with the composition disclosed herein. Ina similar manner, a pharmaceutical composition any of the otherbenzo(iso)oxazolepiperidines disclosed herein and/or any of the otherfatty acids disclosed herein, such as, e.g., an omega-3 fatty acid, anomega-6 fatty acid, an omega-7 fatty acid, an omega-9 fatty acid, or anycombination thereof, may be formulated into a pharmaceutical compositionand administered to the patient as described above. Additionally,administration of other therapeutic compounds disclosed herein, such as,e.g., a 5α reductase inhibitor, a chemotherapeutic agent, ananti-proliferative agent, or any combination thereof may be used in thetreatment of this cancer.

A 67 year old man previously treated for prostate cancer with a hormonedepletion therapy complains of a return of symptoms such as difficultyin urination. After routine history and physical examination, aphysician determines that the cancer in the prostate has increase inmass and has metastasized into the bones. The physician diagnosis theman with a hormone refractory prostate cancer. The man is treatedsystemically by intravenous administration a pharmaceutical compositioncomprising Risperidone and Rumenic acid as disclosed herein. Thepatient's condition is monitored and after about one month aftertreatment, the physician determines that the size of the prostate hasnot increased in size. At three and six month check-ups, the physiciandetermines that there is a decrease in the size of the tumor and thatserum PSA levels are within the normal range. This reduction in tumorsize and/or reduces serum PSA levels indicates successful treatment withthe composition disclosed herein. In a similar manner, a pharmaceuticalcomposition any of the other benzo(iso)oxazolepiperidines disclosedherein and/or any of the other fatty acids disclosed herein, such as,e.g., an omega-3 fatty acid, an omega-6 fatty acid, an omega-7 fattyacid, an omega-9 fatty acid, or any combination thereof, may beformulated into a pharmaceutical composition and administered to thepatient as described above. Additionally, administration of othertherapeutic compounds disclosed herein, such as, e.g., a 5α reductaseinhibitor, a chemotherapeutic agent, an anti-proliferative agent, or anycombination thereof may be used in the treatment of this cancer.

A 61 year old woman complains of a solid mass in her left breast. Afterroutine history and physical examination, a physician diagnosis thewoman with breast cancer. The woman is treated systemically by oraladministration a pharmaceutical composition comprising Risperidone andRumenic acid as disclosed herein. The patient's condition is monitoredand after about one month after treatment, the physician notes that thegrowth of the mass has slowed down. At three and six month check-ups,the physician determines that there is a decrease in the size of thetumor. The reduction in tumor size indicates successful treatment withthe composition disclosed herein. In a similar manner, a pharmaceuticalcomposition any of the other benzo(iso)oxazolepiperidines disclosedherein and/or any of the other fatty acids disclosed herein, such as,e.g., an omega-3 fatty acid, an omega-6 fatty acid, an omega-7 fattyacid, an omega-9 fatty acid, or any combination thereof, may beformulated into a pharmaceutical composition and administered to thepatient as described above. Additionally, administration of othertherapeutic compounds disclosed herein, such as, e.g., a 5α reductaseinhibitor, a chemotherapeutic agent, an anti-proliferative agent, or anycombination thereof may be used in the treatment of this cancer.

A 53 year old woman complains of pelvic pain. After routine history andphysical examination, a physician diagnosis the woman with ovariancancer. The woman is treated systemically by oral administration apharmaceutical composition comprising Risperidone and Rumenic acid asdisclosed herein. The patient's condition is monitored and after aboutone month after treatment, the physician notes that the growth of themalignant tumor has slowed down. At three and six month check-ups, thewoman indicates that the pelvic pain is much reduced and the physiciandetermines that there is a decrease in the size of the tumor. Thereduction in pain and/or tumor size indicates successful treatment withthe composition disclosed herein. In a similar manner, a pharmaceuticalcomposition any of the other benzo(iso)oxazolepiperidines disclosedherein and/or any of the other fatty acids disclosed herein, such as,e.g., an omega-3 fatty acid, an omega-6 fatty acid, an omega-7 fattyacid, an omega-9 fatty acid, or any combination thereof, may beformulated into a pharmaceutical composition and administered to thepatient as described above. Additionally, administration of othertherapeutic compounds disclosed herein, such as, e.g., a 5α reductaseinhibitor, a chemotherapeutic agent, an anti-proliferative agent, or anycombination thereof may be used in the treatment of this cancer.

A 69 year old man complains of chest pain and that it is difficult tobreath and wheezing. After routine history and physical examination, aphysician diagnosis the man with lung cancer. The man is treatedsystemically by intravenous administration a pharmaceutical compositioncomprising Risperidone and Rumenic acid as disclosed herein. Thepatient's condition is monitored and after about one month aftertreatment, the physician notes that the growth of the malignant tumorhas slowed down. At three and six month check-ups, the man indicatesthat the chest pain is reduced, normal breathing has returned, and thephysician determines that there is a decrease in the size of the tumor.The reduction in pain and/or tumor size indicates successful treatmentwith the composition disclosed herein. In a similar manner, apharmaceutical composition any of the other benzo(iso)oxazolepiperidinesdisclosed herein and/or any of the other fatty acids disclosed herein,such as, e.g., an omega-3 fatty acid, an omega-6 fatty acid, an omega-7fatty acid, an omega-9 fatty acid, or any combination thereof, may beformulated into a pharmaceutical composition and administered to thepatient as described above. Additionally, administration of othertherapeutic compounds disclosed herein, such as, e.g., a 5α reductaseinhibitor, a chemotherapeutic agent, an anti-proliferative agent, or anycombination thereof may be used in the treatment of this cancer.

A 20 year old man begins losing hair on his scalp. After routine historyand physical examination, a physician diagnosis the man with androgenicalopecia. The man is treated locally by topical administration apharmaceutical composition comprising Risperidone and Rumenic acid asdisclosed herein. The patient's condition is monitored and after aboutone month after treatment, the physician notes that further loss of hairhas slowed. At three and six month check-ups, the man indicates that hehas noticed regrowth in the areas where hair loss occurred on his scalpand physician determines that there is a further decrease in hair loss.This reduction in hair loss and/or new hair growth indicates successfultreatment with the composition disclosed herein. In a similar manner, apharmaceutical composition any of the other benzo(iso)oxazolepiperidinesdisclosed herein and/or any of the other fatty acids disclosed herein,such as, e.g., an omega-3 fatty acid, an omega-6 fatty acid, an omega-7fatty acid, an omega-9 fatty acid, or any combination thereof, may beformulated into a pharmaceutical composition and administered to thepatient as described above. Additionally, administration of othertherapeutic compounds disclosed herein, such as, e.g., a 5α reductaseinhibitor, may be used in the treatment of this hair loss.

In closing, it is to be understood that although aspects of the presentspecification are highlighted by referring to specific embodiments, oneskilled in the art will readily appreciate that these disclosedembodiments are only illustrative of the principles of the subjectmatter disclosed herein. Therefore, it should be understood that thedisclosed subject matter is in no way limited to a particularmethodology, protocol, and/or reagent, etc., described herein. As such,various modifications or changes to or alternative configurations of thedisclosed subject matter can be made in accordance with the teachingsherein without departing from the spirit of the present specification.Lastly, the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.Accordingly, the present invention is not limited to that precisely asshown and described.

Certain embodiments of the present invention are described herein,including the best mode known to the inventors for carrying out theinvention. Of course, variations on these described embodiments willbecome apparent to those of ordinary skill in the art upon reading theforegoing description. The inventor expects skilled artisans to employsuch variations as appropriate, and the inventors intend for the presentinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedembodiments in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Groupings of alternative embodiments, elements, or steps of the presentinvention are not to be construed as limitations. Each group member maybe referred to and claimed individually or in any combination with othergroup members disclosed herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Unless otherwise indicated, all numbers expressing a characteristic,item, quantity, parameter, property, term, and so forth used in thepresent specification and claims are to be understood as being modifiedin all instances by the term “about.” As used herein, the term “about”means that the characteristic, item, quantity, parameter, property, orterm so qualified encompasses a range of plus or minus ten percent aboveand below the value of the stated characteristic, item, quantity,parameter, property, or term. Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical indication shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and values setting forth the broad scope ofthe invention are approximations, the numerical ranges and values setforth in the specific examples are reported as precisely as possible.Any numerical range or value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Recitation of numerical ranges ofvalues herein is merely intended to serve as a shorthand method ofreferring individually to each separate numerical value falling withinthe range. Unless otherwise indicated herein, each individual value of anumerical range is incorporated into the present specification as if itwere individually recited herein.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the present invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein is intended merely to betterilluminate the present invention and does not pose a limitation on thescope of the invention otherwise claimed. No language in the presentspecification should be construed as indicating any non-claimed elementessential to the practice of the invention.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the present invention so claimed areinherently or expressly described and enabled herein.

All patents, patent publications, and other publications referenced andidentified in the present specification are individually and expresslyincorporated herein by reference in their entirety for the purpose ofdescribing and disclosing, for example, the compositions andmethodologies described in such publications that might be used inconnection with the present invention. These publications are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing in this regard should be construed as an admissionthat the inventors are not entitled to antedate such disclosure byvirtue of prior invention or for any other reason. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents.

1. A method of treating an individual with a cancer, the methodcomprising the step of administering to an individual in need thereof abenzo(iso)oxazolepiperidine and a fatty acid, wherein the fatty acid isan omega-3 fatty acid, an omega-6 fatty acid, an omega-7 fatty acid, anomega-9 fatty acid, or any combination thereof, and whereinadministration the benzo(iso)oxazolepiperidine and the fatty acidreduces a symptom associated with the cancer, thereby treating theindividual.
 2. The method according to claim 1, wherein the amount ofthe benzo(iso)oxazolepiperidine about 0.1 mg/day to about 20 mg/day 3.The method according to claim 1, wherein the amount of thebenzo(iso)oxazolepiperidine is from about 0.01 mg/kg/day to about 0.5mg/kg/day.
 4. The method according to claim 1, wherein thebenzo(iso)oxazolepiperidine is an optionally substituted Iloperidone, anoptionally substituted ocaperidone, an optionally substitutedpaliperidone, an optionally substituted risperidone, or any combinationthereof.
 5. The method according to claim 4, wherein thebenzo(iso)oxazolepiperidine is an optionally substituted risperidone. 6.The method according to claim 5, wherein the optionally substitutedrisperidone is risperidone.
 7. The method according to claim 6, whereinthe amount of the risperidone about 0.1 mg/day to about 20 mg/day
 8. Themethod according to claim 6, wherein the amount of the risperidone isfrom about 0.01 mg/kg/day to about 0.5 mg/kg/day.
 9. The methodaccording to claim 1, wherein the amount of the fatty acid is from about1 mg/day to about 20 mg/day.
 10. The method according to claim 1,wherein the amount of the fatty acid is from about 0.01 mg/kg/day toabout 0.5 mg/kg/day.
 11. The method according to claim 1, wherein theomega-3 fatty acid is Hexadecatrienoic acid, α-Linolenic acid,Stearidonic acid, Eicosatrienoic acid, Eicosatetraenoic acid,Eicosapentaenoic acid, Heneicosapentaenoic acid, Docosapentaenoic acid,Docosahexaenoic acid, Tetracosapentaenoic acid, Tetracosahexaenoic acid,or any combination thereof.
 12. The method according to claim 1, whereinthe omega-6 fatty acid is Linoleic acid, γ-linolenic acid, Calendicacid, Eicosadienoic acid, Dihomo-γ-linolenic acid, Arachidonic acid,Docosadienoic acid, Adrenic acid, Docosapentaenoic acid,Tetracosatetraenoic acid, and Tetracosapentaenoic acid, or anycombination thereof.
 13. The method according to claim 1, wherein theomega-7 fatty acid is 5-Dodecenoic acid, 7-Tetradecenoic acid,9-Hexadecenoic acid, 11-Decenoic acid, 13-Eicosenoic acid, 15-Docosenoicacid, 17-Tetracosenoic acid, and 9Z,11E conjugated Linoleic acid, or anycombination thereof.
 14. The method according to claim 13, wherein theomega-7 fatty acid is 9Z,11E conjugated Linoleic acid.
 15. The methodaccording to claim 14, wherein the amount of the 9Z,11E conjugatedLinoleic acid is from about 1 mg/day to about 20 mg/day.
 16. The methodaccording to claim 14, wherein the amount of the 9Z,11E conjugatedLinoleic acid is from about 0.01 mg/kg/day to about 0.5 mg/kg/day. 17.The method according to claim 1, wherein the omega-9 fatty acid Oleicacid, Elaidic acid, Eicosenoic acid, Mead acid, Erucic acid, Nervonicacid, and Ricinoleic acid, or any combination thereof.
 18. The methodaccording to claim 1, wherein the cancer is a hormone-refractory cancer.19. The method according to claim 1, wherein the cancer is a prostatecancer, a lung cancer, a breast cancer, an ovarian cancer, or testicularcancer.